Methods of synthesizing a prostacyclin analog

ABSTRACT

The present invention provides processes for preparing a prostacyclin analogue of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 10  is a linear or branched C 1-6  alkyl. The processes of the present invention comprise steps that generate improved yields and fewer byproducts than traditional methods. The processes of the present invention employ reagents (e.g., the oxidizing reagent) that are less toxic that those used in the traditional methods (e.g., oxalyl chloride). Many of the processes of the present invention generate intermediates with improved e.e. and chemical purity; thereby eliminating the need of additional chromatography steps. And, the processes of the present invention are scalable to generate commercial quantities of the final compound.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. patent applicationSer. No. 14/650,234, filed Jun. 5, 2015, which is a 35 U.S.C. §371United States National Phase Application of PCT Application Serial No.PCT/US2013/073474, filed Dec. 6, 2013, which claims the benefit of andpriority to U.S. provisional application Ser. Nos. 61/734,672, filedDec. 7, 2012, and 61/777,882, filed Mar. 12, 2013. The entire contentsof the aforementioned disclosures are incorporated herein by referencein their entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to processes and intermediates for thepreparation of prostacyclin analog that are useful for treatinghypertension and other diseases.

BACKGROUND

Prostacyclin derivatives and analogs are useful pharmaceutical compoundspossessing activities such as platelet aggregation inhibition, gastricsecretion reduction, lesion inhibition, vasodilation, andbronchodilation.

Treprostinil is a synthetic prostacyclin derivative currently marketedas an active pharmaceutical ingredient (API) for its ability to inhibitpulmonary arterial hypertension under the trade name Remodulin®.Treprostinil was first described in U.S. Pat. No. 4,306,075.

Prostacyclin derivatives are traditionally synthesized using a varietyof methods that are described in J. Org. Chem. 2004, 69, 1890-1902, Drugof the Future, 2001, 26(4), 364-374, U.S. Pat. Nos. 4,306,075;6,441,245; 6,528,688; 6,700,025; 6,765,117; 6,809,223 and U.S. patentapplication publication nos. 2009/0163738, 2011/0319641 A1, as well asCanadian patent application publication no. 2710726 A1. The entireteachings of these documents are incorporated herein by reference intheir entireties. Also disclosed in these publications are processes andintermediates useful for the preparation of Treprostinil. However, themethods of these teachings suffer from one or more problems includingtoxic oxidation reagents, reduced yields, elevated levels of impurities,poor scalability, and numerous chromatography steps to purifyintermediates and final products. Thus, there remains a need for safe,scalable, efficient, and economical processes for the preparation ofTreprostinil.

SUMMARY OF THE INVENTION

As described herein, the present invention provides processes forpreparing a prostacyclin analogue of Formula IA:

or a pharmaceutically acceptable salt thereof, wherein R¹⁰ is a linearor branched C₁₋₆ alkyl.

The processes of the present invention comprise steps that generateimproved yields and fewer byproducts than traditional methods. Theprocesses of the present invention employ reagents (e.g., the oxidizingreagent) that are less toxic that those used in the traditional methods(e.g., oxalyl chloride). Many of the processes of the present inventiondo not require additional chromatography for purification ofintermediates and generate intermediates with improved e.e. and chemicalpurity. And, the processes of the present invention are scalable togenerate commercial quantities of the final compound.

One aspect of the present invention provides a method of generating acompound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:i) reacting a compound of Formula 9 with an oxidizing agent in thepresence of an organic solvent to generate a compound of Formula 10

wherein R¹ is C₁₋₆ alkyl and the oxidizing agent comprises MnO₂ orDess-Martin periodinane; ii) reacting the compound of Formula 10 with acompound of Formula 5 in the presence of a base and an organic solventto generate a compound of Formula 11, wherein each R² is independentlyselected from C₁₋₆ alkyl or phenyl; and

iii) converting the compound of Formula 11 to the compound of Formula I.

In some implementations, the organic solvent of step i) comprises ahalogenated organic solvent. For example, the organic solvent of step i)comprises dichloromethane, chloroform, or any combination thereof.

In some implementations, the base of step ii) comprises an alkyllithiumreagent. For example, the base of step ii) comprises sec-butyllithium.

In some implementations, the organic solvent of step ii) comprisespentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane,diethyl ether, petro ether, methyl-tert-butylether, or any combinationthereof. For example, the organic solvent of step ii) comprisesmethyl-tert-butylether.

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with SiCl(R²)₃ under basicconditions to generate the compound of Formula 2;

vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generatethe compound of Formula 3; and

vii) converting the compound of Formula 3 to the compound of Formula 5.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:viii) reacting a compound of Formula 11 with an oxidizing agent in thepresence of an organic solvent to generate a compound of Formula 12

wherein R¹ is C₁₋₆ alkyl, each R² is independently selected from C₁₋₆alkyl or phenyl, and the oxidizing agent comprises MnO₂; and ix)converting the compound of Formula 12 to the compound of Formula I.

In some implementations, each of the —OSi(R²)₃ groups in the compoundsof Formulae 11 and 12 is independently selected from

In some implementations, the organic solvent of step viii) comprises ahalogenated organic solvent. In some examples, the halogenated organicsolvent of step viii) comprises dichloromethane, chloroform, or anycombination thereof.

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent in the presence of an organic solventto generate a compound of Formula 10

wherein R¹ is C₁₋₆ alkyl and the oxidizing agent comprises MnO₂ orDess-Martin periodinane; and ii) reacting the compound of Formula 10with a compound of Formula 5

in the presence of a base and an organic solvent to generate a compoundof Formula 11.

In some implementations, the base of step ii) comprises an alkyllithiumreagent. For example, the alkyllithium reagent of step ii) comprisessec-butyllithium.

In some implementations, the organic solvent of step ii) comprisespentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane,diethyl ether, petro ether, methyl-tert-butylether, or any combinationthereof. For example, the organic solvent of step ii) comprisesmethyl-tert-butylether.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:x) reacting a compound of Formula 12 with a reducing agent in thepresence of an organic solvent to generate a compound of Formula 13

wherein the organic solvent comprises THF, R¹ is C₁₋₆ alkyl, and each R²is independently C₁₋₆ alkyl or phenyl; and xi) converting the compoundof Formula 13 to the compound of Formula I.

In some implementations, the reducing agent of step x) comprises achiral borane compound. And, in some examples, the chiral boranecompound is selected from(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole,(4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any combinationthereof.

In some implementations, the organic solvent of step x) furthercomprises toluene.

Some methods further comprise the step of: viii) reacting a compound ofFormula 11 with an oxidizing agent to generate the compound of Formula12, wherein the oxidizing agent comprises MnO₂

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5 inthe presence of a base and an organic solvent to generate a compound ofFormula 11

In some implementations, the oxidizing agent comprises MnO₂ orDess-Martin periodinane.

In some implementations, the base of step ii) comprises an alkyllithiumreagent. For example, the alkyllithium reagent of step ii) comprisessec-butyllithium.

In some implementations, the organic solvent of step ii) comprisespentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane,diethyl ether, petro ether, methyl-tert-butylether, or any combinationthereof. For example, the organic solvent of step ii) comprisesmethyl-tert-butylether.

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with SiCl(R²)₃ under basicconditions to generate the compound of Formula 2;

vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generatethe compound of Formula 3; and

vii) converting the compound of Formula 3 to the compound of Formula 5.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:xii) hydrogenating a compound of Formula 15 in the presence of anorganic solvent (e.g., an alcohol (e.g., methanol, ethanol, or anycombination thereof), an optionally substituted THF (e.g., 2-methyl-THFor THF), EtOAc, or any combination thereof) to generate the compound ofFormula 16

wherein R¹ is C₁₋₆ alkyl and each R² is independently selected from C₁₋₆alkyl or phenyl; and xiii) converting the compound of Formula 16 to thecompound of Formula I.

Some methods further comprise the steps of: x) reacting a compound ofFormula 12 with a reducing agent in the presence of an organic solventto generate a compound of Formula 13

wherein the organic solvent comprises THF; and xiv) converting thecompound of Formula 13 to the compound of Formula 15.

In some implementations, the reducing agent of step x) comprises achiral borane compound. And, in some examples, the chiral boranecompound is selected from(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole,(4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any combinationthereof.

Some methods further comprise the steps of: viii) reacting a compound ofFormula 11 with an oxidizing agent to generate the compound of Formula12, wherein the oxidizing agent comprises MnO₂

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5 inthe presence of a base and an organic solvent to generate a compound ofFormula 11

In some implementations, the oxidizing agent of step i) comprises MnO₂or Dess-Martin periodinane.

In some implementations, the base of step ii) comprises an alkyllithiumreagent. For example, the alkyllithium reagent of step ii) comprisessec-butyllithium.

In some implementations, the organic solvent of step ii) comprisespentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane,diethyl ether, petro ether, methyl-tert-butylether, or any combinationthereof. For example, the organic solvent of step ii) comprisesmethyl-tert-butylether.

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with SiCl(R²)₃ under basicconditions to generate the compound of Formula 2;

vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generatethe compound of Formula 3; and

vii) converting the compound of Formula 3 to the compound of Formula 5.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:xv) reacting a compound of Formula 21 with n-butyllithium in thepresence of an organic solvent and a transition metal catalyst togenerate a compound of Formula 22

wherein R³ is C₁₋₆ alkyl or phenyl; and xvi) converting the compound ofFormula 22 to the compound of Formula I.

In some implementations, the transition metal catalyst of step xv)comprises a compound or complex either of which comprises Cu having a +1oxidation state. For example, the transition metal catalyst of step xv)comprises CuX, wherein X is selected from halogen, acetate, benzoate,cyanide, hydroxide, nitrate, or any combination thereof. In otherexamples, the transition metal catalyst of step xv) comprises CuI.

Some methods further comprise the steps of: xvii) reacting a compound ofFormula 19 with R⁴-substituted benzenesulfonyl chloride under basicconditions to generate a compound of Formula 20, wherein each R⁴ isindependently selected from —H or C₁₋₃ alkyl; and

xviii) reacting the compound of Formula 20 with methanol under basicconditions to generate the compound of Formula 21.

Some methods further comprise the steps of: xix) reacting a compound ofFormula 16 with a reducing agent to generate a compound of Formula 17;

xx) reacting the compound of Formula 17 with Si(R³)₃Cl under basicconditions to generate a compound of Formula 18; and

xxi) selectively deprotecting the compound of Formula 18 to generate thecompound of Formula 19.

Some methods further comprise the steps of: xii) hydrogenating acompound of Formula 15

in the presence of an organic solvent (e.g., an alcohol (e.g., methanol,ethanol, or any combination thereof), an optionally substituted THF(e.g., 2-methyl-THF or THF), EtOAc, or any combination thereof) togenerate the compound of Formula 16.

In some implementations, the hydrogenation of the compound of Formula 15also occurs in the presence of a base (e.g., potassium carbonate orpotassium bicarbonate).

Some methods further comprise the steps of: x) reacting a compound ofFormula 12 with a reducing agent to generate a compound of Formula 13;and

xiv) converting the compound of Formula 13 to the compound of Formula15.

In some implementations, the reducing agent of step x) comprises achiral borane compound. And, in some examples, the chiral boranecompound is selected from(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole,(4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any combinationthereof.

Some methods further comprise the step of: viii) reacting a compound ofFormula 11

with an oxidizing agent to generate the compound of Formula 12, whereinthe oxidizing agent comprises MnO₂.

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5 inthe presence of a base and an organic solvent to generate a compound ofFormula 11

In some implementations, the oxidizing agent of step i) comprises MnO₂or Dess-Martin periodinane.

In some implementations, the base of step ii) comprises an alkyllithiumreagent. For example, the alkyllithium reagent of step ii) comprisessec-butyllithium.

In some implementations, the organic solvent of step ii) comprisespentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane,diethyl ether, petro ether, methyl-tert-butylether, or any combinationthereof. For example, the organic solvent of step ii) comprisesmethyl-tert-butylether.

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having greater than about 99% e.e.;

v) reacting the compound of Formula 1 with SiCl(R²)₃ under basicconditions to generate the compound of Formula 2;

vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generatethe compound of Formula 3; and

vii) converting the compound of Formula 3 to the compound of Formula 5.

Some methods further comprise the steps of: xxii) reacting a compound ofFormula 7 with a 3-haloprop-1-ene in the presence of a base and anorganic solvent to generate a compound of Formula 8; and

xxiii) deprotecting the compound of Formula 8 to generate the compoundof Formula 9.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:xxii) reacting a compound of Formula 7, wherein R¹ is C₁₋₆ alkyl andeach R² is independently selected from C₁₋₆ alkyl or phenyl, with a3-haloprop-1-ene in the presence of a base and an organic solvent togenerate a compound of Formula 8;

xxiii) deprotecting the compound of Formula 8 to generate the compoundof Formula 9, and

xxiv) converting the compound of Formula 9 to the compound of Formula I,

-   wherein the base of step xxii) comprises sec-butyl lithium.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:i) reacting a compound of Formula 9 with an oxidizing agent in thepresence of an organic solvent to generate a compound of Formula 10

wherein R¹ is C₁₋₆ alkyl and the oxidizing agent comprises MnO₂ orDess-Martin periodinane;

-   ii) reacting the compound of Formula 10 with a compound of Formula    5a in the presence of a base and an organic solvent to generate a    compound of Formula 11a; and

iii) converting the compound of Formula 11a to the compound of FormulaI.

In some implementations, the organic solvent of step i) comprises ahalogenated organic solvent. For example, the organic solvent of step i)comprises dichloromethane, chloroform, or any combination thereof.

In some implementations, the base of step ii) comprises an alkyllithiumreagent. For example, the base of step ii) comprises sec-butyllithium.

In some implementations, the organic solvent of step ii) comprisespentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane,diethyl ether, petro ether, methyl-tert-butylether, or any combinationthereof. For example, the organic solvent of step ii) comprisesmethyl-tert-butylether.

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with TBSCl under basic conditionsto generate the compound of Formula 2a;

vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generatethe compound of Formula 3a; and

vii) converting the compound of Formula 3a to the compound of Formula5a.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:viii) reacting a compound of Formula 11a with an oxidizing agent in thepresence of an organic solvent to generate a compound of Formula 12a

wherein R¹ is C₁₋₆ alkyl and the oxidizing agent comprises MnO₂; and ix)converting the compound of Formula 12a to the compound of Formula I.

In some implementations, the organic solvent of step viii) comprises ahalogenated organic solvent. For example, the halogenated organicsolvent of step viii) comprises dichloromethane, chloroform, or anycombination thereof.

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent in the presence of an organic solventto generate a compound of Formula 10

wherein the oxidizing agent comprises MnO₂ or Dess-Martin periodinane;and ii) reacting the compound of Formula 10 with a compound of Formula5a

in the presence of a base and an organic solvent to generate a compoundof Formula 11a.

In some implementations, the organic solvent of step i) comprises ahalogenated organic solvent. For example, the organic solvent of step i)comprises dichloromethane, chloroform, or any combination thereof.

In some implementations, the base of step ii) comprises an alkyllithiumreagent. For example, the base of step ii) comprises sec-butyllithium.

In some implementations, the organic solvent of step ii) comprisespentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane,diethyl ether, petro ether, methyl-tert-butylether, or any combinationthereof. For example, the organic solvent of step ii) comprisesmethyl-tert-butylether.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:x) reacting a compound of Formula 12a with a reducing agent in thepresence of an organic solvent to generate a compound of Formula 13a

wherein the organic solvent comprises THF, R¹ is C₁₋₆ alkyl, and each R²is independently selected from C₁₋₆ alkyl or phenyl; and xi) convertingthe compound of Formula 13 to the compound of Formula I.

In some implementations, the reducing agent of step x) comprises achiral borane compound. And, in some examples, the chiral boranecompound is selected from(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole,(4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any combinationthereof.

In some implementations, the organic solvent of step x) comprises THF.

In some implementations, the organic solvent of step x) furthercomprises toluene.

Some methods further comprise the step of: viii) reacting a compound ofFormula 11a with an oxidizing agent to generate the compound of Formula12a, wherein the oxidizing agent comprises MnO₂

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5a inthe presence of a base and an organic solvent to generate a compound ofFormula 11a

In some implementations, the oxidizing agent of step i) comprises MnO₂or Dess-Martin periodinane.

In some implementations, the base of step ii) comprises an alkyllithiumreagent. For example, the alkyllithium reagent of step ii) comprisessec-butyllithium.

In some implementations, the organic solvent of step ii) comprisespentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane,diethyl ether, petro ether, methyl-tert-butylether, or any combinationthereof. For example, the organic solvent of step ii) comprisesmethyl-tert-butylether.

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with TBSCl under basic conditionsto generate the compound of Formula 2a;

vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generatethe compound of Formula 3a; and

vii) converting the compound of Formula 3a to the compound of Formula5a.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:xii) hydrogenating a compound of Formula 15a in the presence of anorganic solvent (e.g., an alcohol (e.g., methanol, ethanol, or anycombination thereof), an optionally substituted THF (e.g., 2-methyl-THFor THF), EtOAc, or any combination thereof) to generate the compound ofFormula 16a

wherein R¹ is C₁₋₆ alkyl; and xiii) converting the compound of Formula16a to the compound of Formula I.

In some implementations, the hydrogenation of the compound of Formula15a also occurs in the presence of a base (e.g., potassium carbonate orpotassium bicarbonate).

Some methods further comprise the steps of: x) reacting a compound ofFormula 12a with a reducing agent in the presence of an organic solventto generate a compound of Formula 13a

wherein the organic solvent comprises THF; and xiv) converting thecompound of Formula 13a to the compound of Formula 15a.

Some methods further comprise the steps of: viii) reacting a compound ofFormula 11a with an oxidizing agent to generate the compound of Formula12a, wherein the oxidizing agent comprises MnO₂

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5a inthe presence of a base and an organic solvent to generate a compound ofFormula 11a

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with TBSCl under basic conditionsto generate the compound of Formula 2a;

vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generatethe compound of Formula 3a; and

vii) converting the compound of Formula 3a to the compound of Formula5a.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:xv) reacting a compound of Formula 21a with n-butyllithium in thepresence of an organic solvent and a transition metal catalyst togenerate a compound of Formula 22a

wherein R¹ is C₁₋₆ alkyl; and xvi) converting the compound of Formula22a to the compound of Formula I.

In some implementations, the transition metal catalyst of step xv)comprises a compound or complex either of which comprises Cu having a +1oxidation state. For example, the transition metal catalyst of step xv)comprises CuX, wherein X is selected from halogen, acetate, benzoate,cyanide, hydroxide, nitrate, or any combination thereof. In otherexamples, the transition metal catalyst of step xv) comprises CuI.

Some methods further comprise the steps of: xvii) reacting a compound ofFormula 19a with triisopropylbenzenesulfonyl chloride under basicconditions to generate a compound of Formula 20a; and

xviii) reacting the compound of Formula 20a with methanol under basicconditions to generate the compound of Formula 21a.

Some methods further comprise the steps of: xix) reacting a compound ofFormula 16a with a reducing agent to generate a compound of Formula 17a;

xx) reacting the compound of Formula 17a with TBDPSCl under basicconditions to generate a compound of Formula 18a; and

xxi) selectively deprotecting the compound of Formula 18a to generatethe compound of Formula 19a.

Some methods further comprise the step of: xii) hydrogenating a compoundof Formula 15a

in the presence of an organic solvent (e.g., an alcohol (e.g., methanol,ethanol, or any combination thereof), an optionally substituted THF(e.g., 2-methyl-THF or THF), EtOAc, or any combination thereof) togenerate the compound of Formula 16a.

In some implementations, the organic solvent of step xii) is anhydrous(e.g., anhydrous methanol or anhydrous THF).

In some implementations, the hydrogenation of the compound of Formula15a occurs in the presence of a base (e.g., potassium carbonate orpotassium bicarbonate).

Some methods further comprise the steps of: x) reacting a compound ofFormula 12a with a reducing agent to generate a compound of Formula 13a;and

xiv) converting the compound of Formula 13a to the compound of Formula15a.

Some methods further comprise the step of: viii) reacting a compound ofFormula 11a

with an oxidizing agent to generate the compound of Formula 12a, whereinthe oxidizing agent comprises MnO₂.

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5a inthe presence of a base and an organic solvent to generate a compound ofFormula 11a

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with TBSCl under basic conditionsto generate the compound of Formula 2a;

vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generatethe compound of Formula 3a; and

vii) converting the compound of Formula 3a to the compound of Formula5a.

Some methods further comprise the steps of: xxii) reacting a compound ofFormula 7a with a 3-haloprop-1-ene in the presence of a base and anorganic solvent to generate a compound of Formula 8a; and

xxiii) deprotecting the compound of Formula 8a to generate the compoundof Formula 9.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:i) reacting a compound of Formula 9 with an oxidizing agent to generatea compound of Formula 10;

ii) reacting the compound of Formula 10 with a compound of Formula 5a inthe presence of a base and an organic solvent to generate a compound ofFormula 11a;

iv) refluxing the compound of Formula 1a in the presence of methanol togenerate a compound of Formula 1 having an e.e. of greater than about98%:

v) reacting the compound of Formula 1 with TBSCl under basic conditionsto generate the compound of Formula 2a;

vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generatethe compound of Formula 3a;

vii) converting the compound of Formula 3a to the compound of Formula5a;

-   viii) reacting a compound of Formula 11a with an oxidizing agent to    generate the compound of Formula 12a, wherein the oxidizing agent    comprises MnO₂;

x) reacting a compound of Formula 12a with a reducing agent to generatea compound of Formula 13a;

xiv) converting the compound of Formula 13a to the compound of Formula15a;

xii) hydrogenating a compound of Formula 15a in the presence of anorganic solvent (e.g., an alcohol (e.g., methanol, ethanol, or anycombination thereof), an optionally substituted THF (e.g., 2-methyl-THFor THF), EtOAc, or any combination thereof) to generate the compound ofFormula 16a;

xix) reacting a compound of Formula 16a with a reducing agent togenerate a compound of Formula 17a;xx) reacting the compound of Formula 17a with TDPSCl under basicconditions to generate a compound of Formula 18a;

xxi) selectively deprotecting the compound of Formula 18a to generatethe compound of Formula 19a;

xvii) reacting a compound of Formula 19a withtriisopropylbenzenesulfonyl chloride under basic conditions to generatea compound of Formula 20a;

xviii) reacting the compound of Formula 20a with methanol under basicconditions to generate the compound of Formula 21a;

xv) reacting a compound of Formula 21a with n-butyllithium in thepresence of an organic solvent and a transition metal catalyst togenerate a compound of Formula 22a; and

xvi) converting the compound of Formula 22a to the compound of FormulaI.

Some methods further comprise the step of: xxiv) reacting the compoundof Formula I with diethanolamine in the presence of an organic solventto generate the diethanolamine salt of the compound of Formula I.

Another aspect of the present invention provides a compound of Formula21

wherein R¹ is C₁₋₆ alkyl and each R³ is independently C₁₋₆ alkyl orphenyl.

In some embodiments, R¹ is methyl, ethyl, propyl, iso-propyl, butyl,sec-butyl, or tert-butyl.

In other embodiments, the —OSi(R³)₃ group is selected from

In some embodiments, R¹ is methyl and the —OSi(R³)₃ group is

Another aspect of the present invention provides a compound of Formula1a

Another aspect of the present invention provides a method of purifying acompound of Formula 1

comprising the steps of: xxx) reacting a compound of Formula 1 with aderivatizing reagent to generate a precipitate that is substantiallyinsoluble in dichloromethane or mixtures thereof (e.g., a mixture ofdichloromethane and an alkane (e.g., heptane)); xxxi) collecting theprecipitate and refluxing the precipitate in a solvent comprising analcohol to generate the compound of Formula 1 having a chemical purityof about 98% or greater and an e.e. of about 98% or greater; wherein themethod excludes the use of any column chromatography.

In some implementations, the derivitizing reagent comprises3,5-dinitrobenzoyl chloride and the alcohol comprises methanol.

Another aspect of the present invention provides a method of purifying acompound of Formula 9

comprising the steps of: xl) reacting a compound of Formula 9, wherein10 is C₁₋₆ alkyl, with 3,5-dinitrobenzoyl chloride to generate aprecipitate comprising a compound of Formula 9A; and

xli) collecting the precipitate and treating the precipitate with a basein the presence of an alcohol to generate the compound of Formula 9having a chemical purity of about 95% or greater (e.g., about 98% orgreater, or from about 95% to about 99.9%); wherein the method excludesthe use of any column chromatography.

Some methods further comprise the step of: xlii) recrystallizing theprecipitate of step xli).

Another aspect of the present invention provides a method of generatinga compound of Formula 5

wherein each of R² is independently selected from a C₁₋₆ alkyl orphenyl, comprising the steps of:

-   iv) refluxing the compound of Formula 1a in the presence of methanol    to generate a compound of Formula 1 having an e.e. of greater than    about 98%;

v) reacting the compound of Formula 1 with SiCl(R²)₃, wherein each R² isindependently selected from C₁₋₆ alkyl or phenyl, under basic conditionsto generate the compound of Formula 2;

vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generatethe compound of Formula 3;

l) deprotecting the compound Formula 3 under basic condition to generatea compound of Formula 4, wherein each of R⁴ and R⁵ are H or —OSi(R²)₃;and

li) reacting the compound of Formula 4 with SiCl(R²)₃ under basicconditions to generate the compound of Formula 5, wherein the compoundof Formula 5 has a chemical purity of about 98% or greater and an e.e.of about 98% or greater (e.g., from about 99% to about 99.99%).

Another aspect of the present invention provides a method of generatinga compound of Formula 13

wherein R¹ is C₁₋₆ alkyl and each R² is independently selected from C₁₋₆alkyl or phenyl, comprising the step of: x) reacting a compound ofFormula 12 with(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole inthe presence of an organic solvent comprising THF and toluene togenerate a compound of Formula 13

wherein the compound of Formula 13 has a chemical purity of about 97% orgreater and a d.e. of about 97% or greater.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method of generating a compound ofFormula I

or a pharmaceutically acceptable salt thereof.

The present invention also provides novel intermediates that are usefulfor the synthesis of the compound of Formula I.

I. DEFINITIONS

As used herein, the following definitions shall apply unless otherwiseindicated.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As used herein, the term “Treprostinil” refers to(1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]aceticacid having the chemical structure, illustrated below, of the compoundof Formula I

Treprostinil is a synthetic analog of prostacyclin (PGI₂) that isindicated for the treatment of pulmonary arterial hypertension and otherdiseases in patients. Treprostinil is formulated into a variety ofdosage forms including forms suited for i.v. infusion and inhalation.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention.

As used herein, the term “hydroxyl” or “hydroxy” refers to an —OHmoiety.

As used herein the term “aliphatic” encompasses the terms alkyl,alkenyl, alkynyl, each of which being optionally substituted as setforth below.

As used herein, an “alkyl” group refers to a saturated aliphatichydrocarbon group containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms.An alkyl group can be straight or branched. Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or2-ethylhexyl. An alkyl group can be substituted (i.e., optionallysubstituted) with one or more substituents such as halo, phospho,cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic[e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl,alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl,(cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro,cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl,heterocycloalkylaminocarbonyl, arylaminocarbonyl, orheteroarylaminocarbonyl], amino [e.g., aliphaticamino,cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g.,aliphatic-SO₂—], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl,sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy,heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Withoutlimitation, some examples of substituted alkyls include carboxyalkyl(such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl),cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl,(alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as(alkyl-SO₂-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl,or haloalkyl.

As used herein, an “alkenyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at leastone double bond. Like an alkyl group, an alkenyl group can be straightor branched. Examples of an alkenyl group include, but are not limitedto allyl, 1- or 2-isopropenyl, 2-butenyl, and 2-hexenyl. An alkenylgroup can be optionally substituted with one or more substituents suchas halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl],heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl],aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g.,(aliphatic)carbonyl, (cycloaliphatic)carbonyl, or(heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g.,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g.,aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, oraliphaticsulfonylamino], sulfonyl [e.g., alkyl-SO₂—,cycloaliphatic-SO₂—, or aryl-SO₂—], sulfinyl, sulfanyl, sulfoxy, urea,thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl,cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryl oxy,aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, orhydroxy. Without limitation, some examples of substituted alkenylsinclude cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl,aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as(alkyl-SO₂-amino)alkenyl), aminoalkenyl, amidoalkenyl,(cycloaliphatic)alkenyl, or haloalkenyl.

As used herein, an “alkynyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and has atleast one triple bond. An alkynyl group can be straight or branched.Examples of an alkynyl group include, but are not limited to, propargyland butynyl. An alkynyl group can be optionally substituted with one ormore substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy,heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy,cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanylor cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl orcycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SO₂—,aliphaticamino-SO₂—, or cycloaliphatic-SO₂—], amido [e.g.,aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino,heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea,sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic,heterocycloaliphatic, aryl, heteroaryl, acyl [e.g.,(cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino[e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl,(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

As used herein, an “amido” encompasses both “aminocarbonyl” and“carbonylamino”. These terms when used alone or in connection withanother group refer to an amido group such as —N(R^(X))—C(O)—R^(Y) or—C(O)—N(R^(X))₂, when used terminally, and —C(O)—N(R^(X))— or—N(R^(X))—C(O)— when used internally, wherein R^(X) and R^(Y) can bealiphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic,heteroaryl or heteroaraliphatic. Examples of amido groups includealkylamido (such as alkylcarbonylamino or alkylaminocarbonyl),(heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido,(heterocycloalkyl)alkylamido, arylamido, aralkylamido,(cycloalkyl)alkylamido, or cycloalkylamido.

As used herein, an “amino” group refers to —NR^(X)R^(Y) wherein each ofR^(X) and R^(Y) is independently hydrogen, aliphatic, cycloaliphatic,(cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic,(heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl,sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl,((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or(heteroaraliphatic)carbonyl, each of which being defined herein andbeing optionally substituted. Examples of amino groups includealkylamino, dialkylamino, or arylamino. When the term “amino” is not theterminal group (e.g., alkylcarbonylamino), it is represented by—NR^(X)—, where R^(X) has the same meaning as defined above.

As used herein, an “aryl” group used alone or as part of a larger moietyas in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic(e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl,tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyltetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systemsin which the monocyclic ring system is aromatic or at least one of therings in a bicyclic or tricyclic ring system is aromatic. The bicyclicand tricyclic groups include benzofused 2-3 membered carbocyclic rings.For example, a benzofused group includes phenyl fused with two or moreC₄₋₈ carbocyclic moieties. An aryl is optionally substituted with one ormore substituents including aliphatic [e.g., alkyl, alkenyl, oralkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl;alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy;heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl;heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of abenzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl[e.g., (aliphatic)carbonyl; (cycloaliphatic)carbonyl;((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;(heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-SO₂— oramino-SO₂—]; sulfinyl [e.g., aliphatic-S(O)— or cycloaliphatic-S(O)—];sulfanyl [e.g., aliphatic-S—]; cyano; halo; hydroxy; mercapto; sulfoxy;urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, anaryl can be unsubstituted.

Non-limiting examples of substituted aryls include haloaryl [e.g.,mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl[e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and(alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl,(((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl[e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl];(cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g.,(aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl,((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl;(((alkyl sulfonyl)amino)alkyl)aryl;((heterocycloaliphatic)carbonyl)aryl; ((alkyl sulfonyl)alkyl)aryl;(cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl;(trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl;p-halo-m-aminoaryl; or (m-(heterocycloaliphatic)-o-(alkyl))aryl.

As used herein, an “araliphatic” such as an “aralkyl” group refers to analiphatic group (e.g., a C₁₋₄ alkyl group) that is substituted with anaryl group. “Aliphatic,” “alkyl,” and “aryl” are defined herein. Anexample of an araliphatic such as an aralkyl group is benzyl.

As used herein, an “aralkyl” group refers to an alkyl group (e.g., aC₁₋₄ alkyl group) that is substituted with an aryl group. Both “alkyl”and “aryl” have been defined above. An example of an aralkyl group isbenzyl. An aralkyl is optionally substituted with one or moresubstituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl,including carboxyalkyl, hydroxyalkyl, or haloalkyl such astrifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl],(cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, aryl carbonyl amino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, orheteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto,alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

As used herein, a “bicyclic ring system” includes 6-12 (e.g., 8-12 or 9,10, or 11) membered structures that form two rings, wherein the tworings have at least one atom in common (e.g., 2 atoms in common).Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl orbicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclicheteroaryls.

As used herein, a “cycloaliphatic” group encompasses a “cycloalkyl”group and a “cycloalkenyl” group, each of which being optionallysubstituted as set forth below.

As used herein, a “cycloalkyl” group refers to a saturated carbocyclicmono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbonatoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl,octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl,bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl,bicyclo[2.2.2]octyl, adamantyl, or((aminocarbonyl)cycloalkyl)cycloalkyl.

A “cycloalkenyl” group, as used herein, refers to a non-aromaticcarbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or moredouble bonds. Examples of cycloalkenyl groups include cyclopentenyl,1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl,octahydro-naphthyl, cyclohexenyl, bicyclo[2.2.2]octenyl, orbicyclo[3.3.1]nonenyl.

A cycloalkyl or cycloalkenyl group can be optionally substituted withone or more substituents such as phospho, aliphatic [e.g., alkyl,alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic,heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl,heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy,aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,(cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino,(aryl)carbonylamino, (araliphatic)carbonylamino,(heterocycloaliphatic)carbonylamino,((heterocycloaliphatic)aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl[e.g., alkyl-SO₂— and aryl-SO₂—], sulfinyl [e.g., alkyl-S(O)—], sulfanyl[e.g., alkyl-S—], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

As used herein, the term “heterocycloaliphatic” encompassesheterocycloalkyl groups and heterocycloalkenyl groups, each of whichbeing optionally substituted as set forth below.

As used herein, a “heterocycloalkyl” group refers to a 3-10 memberedmono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- orbicyclic) saturated ring structure, in which one or more of the ringatoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examplesof a heterocycloalkyl group include piperidyl, piperazyl,tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl,1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl,octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl,octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl,octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl. A monocyclic heterocycloalkylgroup can be fused with a phenyl moiety to form structures, such astetrahydroisoquinoline, which would be categorized as heteroaryls.

A “heterocycloalkenyl” group, as used herein, refers to a mono- orbicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ringstructure having one or more double bonds, and wherein one or more ofthe ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic andbicyclic heterocycloaliphatics are numbered according to standardchemical nomenclature.

A heterocycloalkyl or heterocycloalkenyl group can be optionallysubstituted with one or more substituents such as phospho, aliphatic[e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic,(cycloaliphatic)aliphatic, heterocycloaliphatic,(heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy,(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy,(araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino,amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino,((cycloaliphatic) aliphatic)carbonylamino, (aryl)carbonylamino,(araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino,((heterocycloaliphatic) aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto,sulfonyl [e.g., alkyl sulfonyl or aryl sulfonyl], sulfinyl [e.g.,alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic,or tricyclic ring system having 4 to 15 ring atoms wherein one or moreof the ring atoms is a heteroatom (e.g., N, O, S, or combinationsthereof) and in which the monocyclic ring system is aromatic or at leastone of the rings in the bicyclic or tricyclic ring systems is aromatic.A heteroaryl group includes a benzofused ring system having 2 to 3rings. For example, a benzofused group includes benzo fused with one ortwo 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,benzo[b]thiophene-yl, quinolinyl, or isoquinolinyl). Some examples ofheteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl,isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine,dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl,indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl,quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl,4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

Without limitation, monocyclic heteroaryls include furyl, thiophene-yl,2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl,pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.Monocyclic heteroaryls are numbered according to standard chemicalnomenclature.

Without limitation, bicyclic heteroaryls include indolizyl, indolyl,isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl,quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl,benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazyl,benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl,phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.Bicyclic heteroaryls are numbered according to standard chemicalnomenclature.

A heteroaryl is optionally substituted with one or more substituentssuch as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic;(cycloaliphatic)aliphatic; heterocycloaliphatic;(heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy;(araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo(on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic ortricyclic heteroaryl); carboxy; amido; acyl [e.g., aliphaticcarbonyl;(cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;(araliphatic)carbonyl; (heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl oraminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g.,aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy;urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, aheteroaryl can be unsubstituted.

Non-limiting examples of substituted heteroaryls include(halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl];(carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl;aminoheteroaryl [e.g., ((alkyl sulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g.,aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl,((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,(((heteroaryl)amino)carbonyl)heteroaryl,((heterocycloaliphatic)carbonyl)heteroaryl, and((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl;(alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g.,(aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g., (alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl;(hydroxy)heteroaryl; ((carboxy)alkyl)heteroaryl;(((dialkyl)amino)alkyl]heteroaryl; (heterocycloaliphatic)heteroaryl;(cycloaliphatic)heteroaryl; (nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkyl sulfonyl)alkyl)heteroaryl;(cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl; or (haloalkyl)heteroaryl [e.g.,trihaloalkylheteroaryl].

A “heteroaraliphatic (such as a heteroaralkyl group) as used herein,refers to an aliphatic group (e.g., a C₁₋₄ alkyl group) that issubstituted with a heteroaryl group. “Aliphatic,” “alkyl,” and“heteroaryl” have been defined above.

A “heteroaralkyl” group, as used herein, refers to an alkyl group (e.g.,a C₁₋₄ alkyl group) that is substituted with a heteroaryl group. Both“alkyl” and “heteroaryl” have been defined above. A heteroaralkyl isoptionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryl oxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,alkylcarbonyloxy, aminocarbonyl, alkylcarbonyl amino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonyl amino, aryl carbonyl amino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonyl amino, heteroarylcarbonylamino,heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

As used herein, “cyclic moiety” and “cyclic group” refer to mono-, bi-,and tri-cyclic ring systems including cycloaliphatic,heterocycloaliphatic, aryl, or heteroaryl, each of which has beenpreviously defined.

As used herein, a “bridged bicyclic ring system” refers to a bicyclicheterocyclicalipahtic ring system or bicyclic cycloaliphatic ring systemin which the rings are bridged. Examples of bridged bicyclic ringsystems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl,3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl. Abridged bicyclic ring system can be optionally substituted with one ormore substituents such as alkyl (including carboxyalkyl, hydroxyalkyl,and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, aryl carbonyl amino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

As used herein, an “acyl” group refers to a formyl group or R^(X)—C(O)—(such as alkyl-C(O)—, also referred to as “alkylcarbonyl”) where R^(X)and “alkyl” have been defined previously. Acetyl and pivaloyl areexamples of acyl groups.

As used herein, an “aroyl” or “heteroaroyl” refers to an aryl-C(O)— or aheteroaryl-C(O)—. The aryl and heteroaryl portion of the aroyl orheteroaroyl is optionally substituted as previously defined.

As used herein, an “alkoxy” group refers to an alkyl-O— group where“alkyl” has been defined previously.

As used herein, a “carbamoyl” group refers to a group having thestructure —O—CO—NR^(X)R^(Y) or —NR^(X)—CO—O—R^(Z), wherein R^(X) andR^(Y) have been defined above and R^(Z) can be aliphatic, aryl,araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

As used herein, a “carboxy” group refers to —COOH, —COOR^(X), —OC(O)H,—OC(O)R^(X), when used as a terminal group; or —OC(O)— or —C(O)O— whenused as an internal group.

As used herein, a “haloaliphatic” group refers to an aliphatic groupsubstituted with 1-3 halogen. For instance, the term haloalkyl includesthe group —CF₃.

As used herein, a “mercapto” group refers to —SH.

As used herein, a “sulfo” group refers to —SO₃H or —SO₃R^(X) when usedterminally or —S(O)₃— when used internally.

As used herein, a “sulfamide” group refers to the structure—NR^(X)—S(O)₂—NR^(Y)R^(Z) when used terminally and —NR^(X)—S(O)₂—NR^(Y)—when used internally, wherein R^(X), R^(Y), and R^(Z) have been definedabove.

As used herein, a “sulfamoyl” group refers to the structure—O—S(O)₂—NR^(Y)R¹ wherein R^(Y) and R^(Z) have been defined above.

As used herein, a “sulfonamide” group refers to the structure—S(O)₂—NR^(X)R^(Y) or —NR^(X)—S(O)₂—R^(Z) when used terminally; or—S(O)₂—NR^(X)— or —NR^(X)—S(O)₂— when used internally, wherein R^(X),R^(Y), and R^(Z) are defined above.

As used herein a “sulfanyl” group refers to —S—R^(X) when usedterminally and —S— when used internally, wherein R^(X) has been definedabove. Examples of sulfanyls include aliphatic-S—, cycloaliphatic-S—,aryl-S—, or the like.

As used herein a “sulfinyl” group refers to —S(O)—R^(X) when usedterminally and —S(O)— when used internally, wherein R^(X) has beendefined above. Exemplary sulfinyl groups include aliphatic-S(O)—,aryl-S(O)—, (cycloaliphatic(aliphatic))-S(O)—, cycloalkyl-S(O)—,heterocycloaliphatic-S(O)—, heteroaryl-S(O)—, or the like.

As used herein, a “sulfonyl” group refers to —S(O)₂—R^(X) when usedterminally and —S(O)₂— when used internally, wherein R^(X) has beendefined above. Exemplary sulfonyl groups include aliphatic-S(O)₂—,aryl-S(O)₂—, (cycloaliphatic(aliphatic))-S(O)₂—, cycloaliphatic-S(O)₂—,heterocycloaliphatic-S(O)₂—, heteroaryl-S(O)₂—,(cycloaliphatic(amido(aliphatic)))-S(O)₂— or the like.

As used herein, a “sulfoxy” group refers to —O—S(O)—R^(X) or—S(O)—O—R^(X), when used terminally and —O—S(O)— or —S(O)—O— when usedinternally, where R^(X) has been defined above.

As used herein, a “halogen” or “halo” group refers to fluorine,chlorine, bromine or iodine.

As used herein, an “alkoxycarbonyl,” which is encompassed by the termcarboxy, used alone or in connection with another group refers to agroup such as alkyl-O—C(O)—.

As used herein, an “alkoxyalkyl” refers to an alkyl group such asalkyl-O-alkyl-, wherein alkyl has been defined above.

As used herein, a “carbonyl” refers to —C(O)—.

As used herein, an “oxo” refers to ═O.

As used herein, the term “phospho” refers to phosphinates andphosphonates. Examples of phosphinates and phosphonates include—P(O)(R^(P))₂, wherein R^(P) is aliphatic, alkoxy, aryloxy,heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl,heteroaryl, cycloaliphatic or amino.

As used herein, an “aminoalkyl” refers to the structure(R^(X))₂N-alkyl-.

As used herein, a “cyanoalkyl” refers to the structure (NC)-alkyl-.

As used herein, a “urea” group refers to the structure—NR^(X)—CO—NR^(Y)R^(Z) and a “thiourea” group refers to the structure—NR^(X)—CS—NR^(Y)R^(Z) when used terminally and —NR^(X)—CO—NR^(Y)— or—NR^(X)—CS—NR^(Y)— when used internally, wherein R^(X), R^(Y), and R^(Z)have been defined above.

As used herein, a “guanidine” group refers to the structure—N═C(N(R^(X)R^(Y)))N(R^(X)R^(Y)) or —NR^(X)—C(═NR^(X))NR^(X)R^(Y)wherein R^(X) and R^(Y) have been defined above.

As used herein, the term “amidino” group refers to the structure—C═(NR^(X))N(R^(X)R^(Y)) wherein R^(X) and R^(Y) have been definedabove.

In general, the term “vicinal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to adjacent carbon atoms.

In general, the term “geminal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to the same carbon atom.

The terms “terminally” and “internally” refer to the location of a groupwithin a substituent. A group is terminal when the group is present atthe end of the substituent not further bonded to the rest of thechemical structure. Carboxyalkyl, i.e., R^(X)O(O)C-alkyl is an exampleof a carboxy group used terminally. A group is internal when the groupis present in the middle of a substituent of the chemical structure.Alkylcarboxy (e.g., alkyl-C(O)O— or alkyl-OC(O)—) and alkylcarboxyaryl(e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxygroups used internally.

As used herein, an “aliphatic chain” refers to a branched or straightaliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups).A straight aliphatic chain has the structure —[CH₂]_(v)—, where v is1-12. A branched aliphatic chain is a straight aliphatic chain that issubstituted with one or more aliphatic groups. A branched aliphaticchain has the structure —[CQQ]_(v)- where Q is independently a hydrogenor an aliphatic group; however, Q shall be an aliphatic group in atleast one instance. The term aliphatic chain includes alkyl chains,alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynylare defined above.

As used herein, “Dess-Martin periodinane” and its abbreviation “DMP” areused interchangeably. DMP refers to1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxo1-3(1H)-one having thestructure

The phrase “optionally substituted” is used interchangeably with thephrase “substituted or unsubstituted.” As described herein, compounds ofthe invention can optionally be substituted with one or moresubstituents, such as are illustrated generally above, or as exemplifiedby particular classes, subclasses, and species of the invention. Asdescribed herein, the variables R¹, R², R³, R⁴, R¹⁰, and other variablescontained in Formulae IA and I described herein encompass specificgroups, such as alkyl and aryl. Unless otherwise noted, each of thespecific groups for the variables R¹, R², R³, R⁴, R¹⁰, and othervariables contained therein can be optionally substituted with one ormore substituents described herein. Each substituent of a specific groupis further optionally substituted with one to three of halo, cyano, oxo,alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic,heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl. For instance, analkyl group can be substituted with alkylsulfanyl and the alkylsulfanylcan be optionally substituted with one to three of halo, cyano, oxo,alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As anadditional example, the cycloalkyl portion of a(cycloalkyl)carbonylamino can be optionally substituted with one tothree of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. Whentwo alkoxy groups are bound to the same atom or adjacent atoms, the twoalkoxy groups can form a ring together with the atom(s) to which theyare bound.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen atoms in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group can have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure can be substituted with more than onesubstituent selected from a specified group, the substituent can beeither the same or different at every position. A ring substituent, suchas a heterocycloalkyl, can be bound to another ring, such as acycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings shareone common atom. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds.

The phrase “stable or chemically feasible,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

As used herein, “chemical purity” refers to the degree to which asubstance, i.e., the desired product or intermediate, is undiluted orunmixed with extraneous material such as chemical byproducts.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays, or as therapeutic agents.

Chemical structures and nomenclature are derived from ChemDraw, version11.0.1, Cambridge, Mass.

It is noted that the use of the descriptors “first”, “second”, “third”,or the like is used to differentiate separate elements (e.g., solvents,reaction steps, processes, reagents, or the like) and may or may notrefer to the relative order or relative chronology of the elementsdescribed.

II. COMMONLY USED ABBREVIATIONS

The following abbreviations are used:

PG protecting group

LG leaving group

DCM dichloromethane

Ac acetyl

THF tetrohydrofuran

TMS trimethylsilyl

TBS tert-butyldimethylsilyl

TIPS tri-iso-propylsilyl

TBDPS tert-butyldiphenylsilyl

TOM tri-iso-propylsilyloxymethyl

DMP Dess-Martin periodinane

IBX 2-iodoxybenzoic acid

DMF dimethylformamide

MTBE methyl-tert-butylether

TBAF tetra-n-butylammonium fluoride

d.e. diastereomeric excess

e.e. enantiomeric excess

EtOAc ethyl acetate

DMSO dimethyl sulfoxide

MeCN acetonitrile

TCA trichloroacetic acid

ATP adenosine triphosphate

EtOH ethanol

Ph phenyl

Me methyl

Et ethyl

Bu butyl

iPr isopropyl

tBu tertbutyl

DEAD diethylazodicarboxylate

HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

DTT dithiothreitol

MOPS 4-morpholinepropanesulfonic acid

NMR nuclear magnetic resonance

HPLC high performance liquid chromatography

LCMS liquid chromatography-mass spectrometry

TLC thin layer chromatography

Rt retention time

HOBt hydroxybenzotriazole

Ms mesyl

Ts tosyl

Tf triflyl

Bs besyl

Ns nosyl

Cbz carboxybenzyl

Moz p-methoxybenzyl carbonyl

Boc tert-butyloxycarbonyl

Fmoc 9-fluorenylmethyloxycarbonyl

Bz benzoly

Bn benzyl

PMB p-methoxybenzyl

DMPM 3,4-dimethoxybenzyl

PMP p-methoxyphenyl

III. METHODS OF SYNTHESIS

One aspect of the present invention provides a method of generating acompound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:i) reacting a compound of Formula 9 with an oxidizing agent in thepresence of an organic solvent to generate a compound of Formula 10

wherein R¹ is C₁₋₆ alkyl and the oxidizing agent comprises MnO₂ orDess-Martin periodinane;

-   ii) reacting the compound of Formula 10 with a compound of Formula 5    in the presence of a base and an organic solvent to generate a    compound of Formula 11, wherein each R² is independently selected    from C₁₋₆ alkyl or phenyl; and

iii) converting the compound of Formula 11 to the compound of Formula I.

A. Step i)

Step i) comprises reacting a compound of Formula 9 with an oxidizingagent in the presence of an organic solvent to generate a compound ofFormula 10

wherein R¹ is C₁₋₆ alkyl.

In some implementations, R¹ is methyl, ethyl, propyl, iso-propyl, butyl,sec-butyl, or tert-butyl. For example, R¹ is methyl.

In some implementations, the oxidizing agent of step i) comprisesmanganese(IV)oxide, i.e., MnO₂, DMP, or IBX. For example, the oxidizingagent comprises MnO₂ or DMP. And, in some instances, the oxidizing agentcomprises MnO₂.

The organic solvent of step i) is any suitable solvent that is capableof substantially dissolving the compound of Formula 9 and issubstantially inert when combined with the oxidizing agent and thecompound of Formula 9. In some implementations, the organic solvent ofstep i) comprises a halogenated organic solvent. For example, thehalogenated organic solvent comprises dichloromethane, i.e., methylenechloride, chloroform, or any combination thereof. In otherimplementations, the organic solvent (e.g., dichloromethane) isanhydrous.

In some implementations, the reaction of step i) is performed at atemperature from about 10° C. to about 40° C. For example, the reactionof step i) is performed at room temperature.

In other implementations, the reaction of step i) is performed underagitation, e.g., stirring.

In some implementations, the reaction of step i) is performed under aninert gas (e.g., nitrogen gas).

In other implementations, the reaction of step i) is about 99% complete(e.g., from about 95% to about 99.9% complete after about 15 hrs (e.g.from about 14 to about 18 hrs).

In some implementations, step i) generates the compound of Formula 10,having a yield of greater than about 95% (e.g., from about 95% to about99.9% or about 99%).

B. Step ii)

Step ii) comprises reacting the compound of Formula 10 with a compoundof Formula 5 in the presence of a base and an organic solvent togenerate a compound of Formula 11, wherein each R² is independentlyselected from C₁₋₆ alkyl or phenyl.

In some implementations, the base comprises an alkyllithium reagent.Examples of alkyllithium reagents include butyllithium, hexyllithium,sec-butyllithium, and methyllithium. In some instances, the basecomprises sec-butyllithium.

Organic solvents that are useful in the reaction of step ii) comprisealkanes, cyclic alkanes, heterocycles (e.g., THF, 1,4-dioxane, or anycombination thereof), ethers, or any combination thereof.

In some implementations, the organic solvent of step ii) comprisespentane, hexane, cyclohexane, heptane, THF, 1,4-dioxane, diethyl ether,petro ether, MTBE, or any combination thereof. For example, the organicsolvent of step ii) comprises MTBE.

In other implementations, the organic solvent of step ii) is anhydrous(e.g., anhydrous MTBE).

And, in some implementations, the base of step ii) comprisessec-butyllithium, and the organic solvent of step ii) comprises MTBE.

In some implementations, the compound of Formula 5 has an e.e. of about98% or greater (e.g., from about 98.0% to about 99.9%). In otherimplementations, the compound of Formula 5 has a chemical purity ofabout 95% or greater (e.g., from about 97% to about 99.9%).

In some implementations, the reaction of step ii) is performed at atemperature from about −80° C. to about 30° C. (e.g., from about −78° C.to about room temperature).

In other implementations, the reaction of step ii) is performed underagitation, e.g., stirring.

In some implementations, the reaction of step ii) is performed under aninert gas (e.g., nitrogen gas).

C. Additional Steps

Steps iv)-vii) may optionally be performed with other steps describedherein to generate the compound of Formula I.

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with SiCl(R²)₃ under basicconditions to generate the compound of Formula 2;

vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generatethe compound of Formula 3; and

vii) converting the compound of Formula 3 to the compound of Formula 5.

Step iv) is an efficient stereoselective method for generating thecompound of Formula 1 having an e.e. of greater than 98% that does notrequire additional chromatography. Moreover, in some implementations,step iv) generates the compound of Formula 1 with a yield of at leastabout 90% (e.g., at least about 91%, or about 92%).

In some implementations, the refluxing of the compound of Formula 1aoccurs in the presence of an alcohol (e.g., methanol, ethanol, or anycombination thereof). In other implementations, the compound of Formula1a undergoes reflux in the presence of methanol (e.g., anhydrousmethanol).

In other implementations, the compound of Formula 1a is heated to refluxunder an inert gas (e.g., nitrogen).

And, in some implementations, the compound of Formula 1a is heated toreflux for a period of about 1 to about 3 hrs (e.g., about 2 hrs).

Step v) comprises the protection of the hydroxy functional group of thecompound of Formula 1 under basic conditions to generate the alkylsilylether compound of Formula 2.

In some implementations, the base of step v) comprises a nitrogen base.In some examples, the nitrogen base comprises Et₃N, imidazole,piperidine, piperazine, any combination thereof, or the like. Forinstance, the base of step v) comprises imidazole.

In some implementations, the SiCl(R²)₃ reagent of step v) compriseschloro-tert-butyldimethylsilane (TBS-Cl), tert-butylchlorodiphenylsilane (TBDPS-Cl), chlorotrimethylsilane (TMS-Cl),triisopropylsilyloxymethyl chloride (TOM-Cl), orchlorotriisopropylsilane (TIPS-Cl).

In some implementations, the 1-TMS-1-propyne of step vi) is firstreacted with an alkyllithium reagent followed by the reaction with thecompound of Formula 2.

The present invention provides a method of generating a compound ofFormula 5

wherein each R² is independently selected from a C₁₋₆ alkyl or phenyl,comprising the steps of: iv) refluxing the compound of Formula 1a in thepresence of methanol to generate a compound of Formula 1 having an e.e.of greater than about 98% (e.g., greater than about 98.5%, greater thanabout 99% or from about 98.5% to about 99.9%);

v) reacting the compound of Formula 1 with SiCl(R²)₃, wherein each R² isindependently selected from C₁₋₆ alkyl or phenyl, under basic conditionsto generate the compound of Formula 2;

vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generatethe compound of Formula 3;

l) deprotecting the compound Formula 3 under basic condition to generatea compound of Formula 4, wherein each of R⁴ and R⁵ are H or —OSi(R²)₃;and

li) reacting the compound of Formula 4 with SiCl(R²)₃ under basicconditions to generate the compound of Formula 5, wherein the compoundof Formula 5 has a chemical purity of about 98% or greater (e.g.,greater than about 98.5%, greater than about 99% or from about 98.5% toabout 99.9%) and an e.e. of about 98% or greater (e.g., from about 99%to about 99.99%).

In implementations, the compound of Formula 5 has a chemical purity ofabout 95% or greater (e.g., from about 97% to about 99.9% or about 99%or greater) and an e.e. of about 98% or greater (e.g., about 99% orgreater). In some implementations, the compound of Formula 5 has an e.e.of ˜100%, e.g., about 98% or greater, about 99% or greater, or greaterthan 99%.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:viii) reacting a compound of Formula 11 with an oxidizing agent in thepresence of an organic solvent to generate a compound of Formula 12

wherein R¹ is C₁₋₆ alkyl, each R² is independently selected from C₁₋₆alkyl or phenyl, and the oxidizing agent comprises MnO₂; and ix)converting the compound of Formula 12 to the compound of Formula I.

D. Step viii)

The reaction of step viii) accomplishes the oxidation of the compound ofFormula 11 to generate the compound of Formula 12 using an oxidizingagent that possesses a reduced toxicity than traditional chromium basedoxidation agents (e.g., PCC).

In some implementations, each of the —OSi(R²)₃ groups in the compoundsof Formulae 11 and 12 is independently selected from

In some implementations, the organic solvent of step viii) comprises ahalogenated organic solvent. In some examples, the halogenated organicsolvent of step viii) comprises dichloromethane, chloroform, or anycombination thereof. In other examples, the organic solvent of stepviii) (e.g., dichloromethane) is anhydrous.

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent in the presence of an organic solventto generate a compound of Formula 10

wherein R¹ is C₁₋₆ alkyl and the oxidizing agent comprises MnO₂ orDess-Martin periodinane; and ii) reacting the compound of Formula 10with a compound of Formula 5

in the presence of a base and an organic solvent to generate a compoundof Formula 11.

Steps i) and ii) are described, in detail, above.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:x) reacting a compound of Formula 12 with a reducing agent in thepresence of an organic solvent to generate a compound of Formula 13

wherein the organic solvent comprises THF, R¹ is C₁₋₆ alkyl, and R² isindependently selected from C₁₋₆ alkyl or phenyl; and xi) converting thecompound of Formula 13 to the compound of Formula I.

E. Step x)

In some implementations, the reducing agent of step x) comprises achiral borane compound. In some implementations, the chiral boranecompound of step x) reacts with the compound of Formula 12 to generatethe compound of Formula 13 with a d.e. of about 97% or greater (e.g.,about 97.5% of greater). In other implementations, the chiral boranereducing agent is formed in situ or ex situ. And, in some examples, thechiral borane compound is selected from(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-1-butyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,(R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaborole,(4S)-2-methyl-4,5,5-triphenyl-1,3,2-oxazaborolidine, or any combinationthereof.

In some implementations, the organic solvent of step x) furthercomprises toluene.

And, in some implementations, the organic solvent of step x) isanhydrous.

Some methods further comprise the step of: viii) reacting a compound ofFormula 11 with an oxidizing agent to generate the compound of Formula12, wherein the oxidizing agent comprises MnO₂

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5 inthe presence of a base and an organic solvent to generate a compound ofFormula 11

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with SiCl(R²)₃ under basicconditions to generate the compound of Formula 2;

vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generatethe compound of Formula 3; and

vii) converting the compound of Formula 3 to the compound of Formula 5.

Each of steps i), ii), and iv)-viii) is discussed above.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:xii) hydrogenating a compound of Formula 15 in the presence of anorganic solvent (e.g., an alcohol (e.g., methanol, ethanol, or anycombination thereof), an optionally substituted THF (e.g., 2-methyl-THFor THF), EtOAc, or any combination thereof) to generate the compound ofFormula 16

wherein R¹ is C₁₋₆ alkyl and each R² is independently selected from C₁₋₆alkyl or phenyl; and xiii) converting the compound of Formula 16 to thecompound of Formula I.

F. Step xii)

Step xii) comprises the improved hydrogenation of the compound ofFormula 15 to generate the compound of Formula 16. Some implementationscomprise the hydrogenation of the compound of Formula 15 in the presenceof an alcohol (e.g., methanol or ethanol), optionally substituted THF(e.g., THF or 2-Me-THF), or any combination thereof to generate thecompound of Formula 16. In other implementations, the hydrogenation ofthe compound of Formula 15 occurs in the presence of an alcohol (e.g.,methanol or ethanol), optionally substituted THF (e.g., THF or2-Me-THF), or any combination thereof and a base (e.g., potassiumcarbonate or potassium bicarbonate).

The substitution of methanol for the traditional ethanol in step xii)produces an improved yield (e.g., at least about 88%) and improvedchemical purity for the compound of Formula 16.

Some methods further comprise the steps of: x) reacting a compound ofFormula 12 with a reducing agent in the presence of an organic solventto generate a compound of Formula 13

wherein the organic solvent comprises THF; and xiv) converting thecompound of Formula 13 to the compound of Formula 15.

Some methods further comprise the steps of: viii) reacting a compound ofFormula 11 with an oxidizing agent to generate the compound of Formula12, wherein the oxidizing agent comprises MnO₂

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5 inthe presence of a base and an organic solvent to generate a compound ofFormula 11

In some implementations, the oxidizing agent of step i) comprises MnO₂or Dess-Martin periodinane.

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with SiCl(R²)₃ under basicconditions to generate the compound of Formula 2;

vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generatethe compound of Formula 3; and

vii) converting the compound of Formula 3 to the compound of Formula 5.

Each of steps i), ii), iv), v)-viii), x), and xiv) is discussed above.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:xv) reacting a compound of Formula 21 with n-butyllithium in thepresence of an organic solvent and a transition metal catalyst togenerate a compound of Formula 22

wherein R³ is C₁₋₆ alkyl or phenyl; and xvi) converting the compound ofFormula 22 to the compound of Formula I.

G. Step xv)

Step xv) generates a yield of at least about 70% (e.g., at least about75%, at least about 80%, or about 82%) for the compound of Formula 22.

In some implementations, the reaction of step xv) is conducted at atemperature of from about −80° C. to about −20° C. (e.g., from about−78° C. to about −30° C.).

In some implementations, the transition metal catalyst of step xv)comprises copper having a +1 oxidation state. For example, thetransition metal catalyst comprises a copper compound or a coppercomplex wherein the Cu has a +1 oxidation state. In other examples, thetransition metal catalyst of step xv) comprises CuX, wherein X isselected from halogen, acetate, benzoate, cyanide, hydroxide, nitrate,or any combination thereof. In other examples, the transition metalcatalyst of step xv) comprises CuI.

Some methods further comprise the steps of: xvii) reacting a compound ofFormula 19 with R⁴-substituted benzenesulfonyl chloride under basicconditions to generate a compound of Formula 20, wherein each R⁴ isindependently selected from —H or C₁₋₃ alkyl; and

xviii) reacting the compound of Formula 20 with methanol under basicconditions to generate the compound of Formula 21.

In some implementations, the R⁴-substituted benzenesulfonyl chloride ofstep xvii) is 2-mesitylenesulfonyl chloride(2,4,6-trimethylbenzenesulfonyl chloride) or tosyl chloride (TsCl).

Some methods further comprise the steps of: xix) reacting a compound ofFormula 16 with a reducing agent to generate a compound of Formula 17;

xx) reacting the compound of Formula 17 with Si(R³)₃Cl under basicconditions to generate a compound of Formula 18; and

xxi) selectively deprotecting the compound of Formula 18 to generate thecompound of Formula 19.

Some methods further comprise the steps of: xii) hydrogenating acompound of Formula 15

in the presence of an organic solvent (e.g., an alcohol (e.g., methanol,ethanol, or any combination thereof), an optionally substituted THF(e.g., 2-methyl-THF or THF), EtOAc, or any combination thereof) togenerate the compound of Formula 16.

In some implementations, the hydrogenation of the compound of Formula 15occurs in the presence of a base (e.g., potassium carbonate or potassiumbicarbonate).

Some methods further comprise the steps of: x) reacting a compound ofFormula 12 with a reducing agent to generate a compound of Formula 13;and

xiv) converting the compound of Formula 13 to the compound of Formula15.

Some methods further comprise the step of: viii) reacting a compound ofFormula 11

with an oxidizing agent to generate the compound of Formula 12, whereinthe oxidizing agent comprises MnO₂.

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5 inthe presence of a base and an organic solvent to generate a compound ofFormula 11

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having greater than about 99% e.e.;

v) reacting the compound of Formula 1 with SiCl(R²)₃ under basicconditions to generate the compound of Formula 2;

vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generatethe compound of Formula 3; and

vii) converting the compound of Formula 3 to the compound of Formula 5.

Steps i), ii), iv)-viii), x), xii), and xiv) are discussed above.

The present invention also provides a method of generating a compound ofFormula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:xxii) reacting a compound of Formula 7, wherein R¹ is C₁₋₆ alkyl and R²is independently selected from C₁₋₆ alkyl or phenyl, with a3-haloprop-1-ene in the presence of a base and an organic solvent togenerate a compound of Formula 8;

xxiii) deprotecting the compound of Formula 8 to generate the compoundof Formula 9, and

xxiv) converting the compound of Formula 9 to the compound of Formula I,wherein the base of step xxii) comprises sec-butyl lithium.

H. Step xxii)

The reaction of step xxii) generates the compound of Formula 8 withimproved chemical purity without additional chromatography steps.

In some implementations, the reaction of step xxii) is conducted at roomtemperature (e.g., from about 20° C. to about 30° C.) for a period ofabout 2 hrs (e.g., from about 1.5 to about 2.5 hrs) then cooled to atemperature of about 0° C. (e.g., from about −5° C. to about 5° C.)under stirring.

In some implementations, the organic solvent of step xxii) comprises oneor more alkanes. For example, the organic solvent of step xxii)comprises heptanes, cyclohexane, or any combination thereof. In otherimplementations, the organic solvent of step xxii) comprises MTBE.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:i) reacting a compound of Formula 9 with an oxidizing agent in thepresence of an organic solvent to generate a compound of Formula 10

wherein R¹ is C₁₋₆ alkyl and the oxidizing agent comprises MnO₂ orDess-Martin periodinane;

-   ii) reacting the compound of Formula 10 with a compound of Formula    5a in the presence of a base and an organic solvent to generate a    compound of Formula 11a; and

iii) converting the compound of Formula 11a to the compound of FormulaI.

Steps i) and ii) are discussed in detail above.

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with TBSCl under basic conditionsto generate the compound of Formula 2a;

vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generatethe compound of Formula 3a; and

vii) converting the compound of Formula 3a to the compound of Formula5a.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:viii) reacting a compound of Formula 11a with an oxidizing agent in thepresence of an organic solvent to generate a compound of Formula 12a

wherein R¹ is C₁₋₆ alkyl and the oxidizing agent comprises MnO₂; and ix)converting the compound of Formula 12a to the compound of Formula I.

Step viii) is discussed above.

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent in the presence of an organic solventto generate a compound of Formula 10

wherein the oxidizing agent comprises MnO₂ or Dess-Martin periodinane;and ii) reacting the compound of Formula 10 with a compound of Formula5a

in the presence of a base and an organic solvent to generate a compoundof Formula 11a.

Steps i) and ii) are discussed in detail above.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:x) reacting a compound of Formula 12a with a reducing agent in thepresence of an organic solvent to generate a compound of Formula 13a

wherein the organic solvent comprises THF, R¹ is C₁₋₆ alkyl, and each R²is independently selected from C₁₋₆ alkyl or phenyl; and xi) convertingthe compound of Formula 13 to the compound of Formula I.

Steps x) and xi) are discusses in detail above.

Some methods further comprise the step of: viii) reacting a compound ofFormula 11a with an oxidizing agent to generate the compound of Formula12a, wherein the oxidizing agent comprises MnO₂

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5a inthe presence of a base and an organic solvent to generate a compound ofFormula 11a

In some implementations, the oxidizing agent of step i) comprises MnO₂or Dess-Martin periodinane.

In some implementations, the base of step ii) comprises an alkyllithiumreagent. For example, the alkyllithium reagent of step ii) comprisessec-butyllithium.

In some implementations, the organic solvent of step ii) comprisespentane, hexane, cyclohexane, heptane, tetrahydrofuran, 1,4-dioxane,diethyl ether, petro ether, methyl-tert-butylether, or any combinationthereof. For example, the organic solvent of step ii) comprisesmethyl-tert-butylether.

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with TBSCl under basic conditionsto generate the compound of Formula 2a;

vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generatethe compound of Formula 3a; and

vii) converting the compound of Formula 3a to the compound of Formula5a.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:xii) hydrogenating a compound of Formula 15a in the presence of anorganic solvent (e.g., an alcohol (e.g., methanol, ethanol, or anycombination thereof), an optionally substituted THF (e.g., 2-methyl-THFor THF), EtOAc, or any combination thereof) to generate the compound ofFormula 16a

wherein R¹ is C₁₋₆ alkyl; and xiii) converting the compound of Formula16a to the compound of Formula I.

In some implementations, the hydrogenation of the compound of Formula15a occurs in the presence of a base (e.g., potassium carbonate orpotassium bicarbonate).

Some methods further comprise the steps of: x) reacting a compound ofFormula 12a with a reducing agent in the presence of an organic solventto generate a compound of Formula 13a

wherein the organic solvent comprises THF; and xiv) converting thecompound of Formula 13a to the compound of Formula 15a.

Some methods further comprise the steps of: viii) reacting a compound ofFormula 11a with an oxidizing agent to generate the compound of Formula12a, wherein the oxidizing agent comprises MnO₂

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5a inthe presence of a base and an organic solvent to generate a compound ofFormula 11a

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with TBSCl under basic conditionsto generate the compound of Formula 2a;

vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generatethe compound of Formula 3a; and

vii) converting the compound of Formula 3a to the compound of Formula5a.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:xv) reacting a compound of Formula 21a with n-butyllithium in thepresence of an organic solvent and a transition metal catalyst togenerate a compound of Formula 22a

wherein R¹ is C₁₋₆ alkyl; and xvi) converting the compound of Formula22a to the compound of Formula I.

In some implementations, the transition metal catalyst of step xv)comprises a compound or complex either of which comprises Cu having a +1oxidation state. For example, the transition metal catalyst of step xv)comprises CuX, wherein X is selected from halogen, acetate, benzoate,cyanide, hydroxide, nitrate, or any combination thereof. In otherexamples, the transition metal catalyst of step xv) comprises CuI.

Some methods further comprise the steps of: xvii) reacting a compound ofFormula 19a with triisopropylbenzenesulfonyl chloride under basicconditions to generate a compound of Formula 20a; and

xviii) reacting the compound of Formula 20a with methanol under basicconditions to generate the compound of Formula 21a.

Some methods further comprise the steps of: xix) reacting a compound ofFormula 16a with a reducing agent to generate a compound of Formula 17a;

xx) reacting the compound of Formula 17a with TBDPSCl under basicconditions to generate a compound of Formula 18a; and

xxi) selectively deprotecting the compound of Formula 18a to generatethe compound of Formula 19a.

Some methods further comprise the step of: xii) hydrogenating a compoundof Formula 15a

in the presence of an organic solvent (e.g., an alcohol (e.g., methanol,ethanol, or any combination thereof), an optionally substituted THF(e.g., 2-methyl-THF or THF), EtOAc, or any combination thereof) togenerate the compound of Formula 16a.

In some implementations, the hydrogenation of the compound of Formula15a occurs in the presence of a base (e.g., potassium carbonate orpotassium bicarbonate).

Some methods further comprise the steps of: x) reacting a compound ofFormula 12a with a reducing agent to generate a compound of Formula 13a;and

xiv) converting the compound of Formula 13a to the compound of Formula15a.

Some methods further comprise the step of: viii) reacting a compound ofFormula 11a

with an oxidizing agent to generate the compound of Formula 12a, whereinthe oxidizing agent comprises MnO₂.

Some methods further comprise the steps of: i) reacting a compound ofFormula 9 with an oxidizing agent to generate a compound of Formula 10;and

ii) reacting the compound of Formula 10 with a compound of Formula 5a inthe presence of a base and an organic solvent to generate a compound ofFormula 11a

Some methods further comprise the steps of: iv) refluxing the compoundof Formula 1a in the presence of methanol to generate a compound ofFormula 1 having an e.e. of greater than about 98%;

v) reacting the compound of Formula 1 with TBSCl under basic conditionsto generate the compound of Formula 2a;

vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generatethe compound of Formula 3a; and

vii) converting the compound of Formula 3a to the compound of Formula5a.

Some methods further comprise the steps of: xxii) reacting a compound ofFormula 7a with a 3-haloprop-1-ene in the presence of a base and anorganic solvent to generate a compound of Formula 8a; and

xxiii) deprotecting the compound of Formula 8a to generate the compoundof Formula 9.

Another aspect of the present invention provides a method of generatinga compound of Formula I

or a pharmaceutically acceptable salt thereof, comprising the steps of:i) reacting a compound of Formula 9 with an oxidizing agent to generatea compound of Formula 10;

ii) reacting the compound of Formula 10 with a compound of Formula 5a inthe presence of a base and an organic solvent to generate a compound ofFormula 11a;

iv) refluxing the compound of Formula 1a in the presence of methanol togenerate a compound of Formula 1 having an e.e. of greater than about98%;

v) reacting the compound of Formula 1 with TBSCl under basic conditionsto generate the compound of Formula 2a;

vi) reacting the compound of Formula 2a with 1-TMS-1-propyne to generatethe compound of Formula 3a;

vii) converting the compound of Formula 3a to the compound of Formula5a;

-   viii) reacting a compound of Formula 11a with an oxidizing agent to    generate the compound of Formula 12a, wherein the oxidizing agent    comprises MnO₂;

x) reacting a compound of Formula 12a with a reducing agent to generatea compound of Formula 13a;

xiv) converting the compound of Formula 13a to the compound of Formula15a;

xii) hydrogenating a compound of Formula 15a in the presence of anorganic solvent (e.g., an alcohol (e.g., methanol, ethanol, or anycombination thereof), an optionally substituted THF (e.g., 2-methyl-THFor THF), EtOAc, or any combination thereof) to generate the compound ofFormula 16a;

xix) reacting a compound of Formula 16a with a reducing agent togenerate a compound of Formula 17a;xx) reacting the compound of Formula 17a with TDPSCl under basicconditions to generate a compound of Formula 18a;

xxi) selectively deprotecting the compound of Formula 18a to generatethe compound of Formula 19a;

xvii) reacting a compound of Formula 19a withtriisopropylbenzenesulfonyl chloride under basic conditions to generatea compound of Formula 20a;

xviii) reacting the compound of Formula 20a with methanol under basicconditions to generate the compound of Formula 21a;

xv) reacting a compound of Formula 21a with n-butyllithium in thepresence of an organic solvent and a transition metal catalyst togenerate a compound of Formula 22a; and

xvi) converting the compound of Formula 22a to the compound of FormulaI.

In some implementations, the hydrogenation of the compound of Formula15a occurs in the presence of a base (e.g., potassium carbonate orpotassium bicarbonate).

Some methods further comprise the step of: xxiv) reacting the compoundof Formula I with diethanolamine in the presence of an organic solventto generate the diethanolamine salt of the compound of Formula I.

Some methods further comprise the step of: xxva) treating the compoundof Formula I with an alkali metal hydroxide (e.g., NaOH, KOH, or like,or any combination thereof) in the presence of an alcohol (e.g.,ethanol, methanol, iso-propanol, or any combination thereof) to generatethe alkali metal salt (e.g., Na salt) of the compound of Formula I.

In some implementations, the alkali metal hydroxide comprises NaOH.

In other implementations, the alcohol comprises ethanol.

Alternatively, some methods further comprise the step of: xxvi) treatingthe compound of Formula 25

wherein R² is defined above, with an alkali metal hydroxide (e.g., NaOH,KOH, or like, or any combination thereof), in the presence of an alcoholand water to generate the alkali metal salt (e.g., Na salt) of thecompound of Formula I.

In some implementations, the alcohol comprises methanol.

Some methods further comprise the step of: xxvii) recrystallizing thediethanolamine salt of the compound of Formula I to generate a firstpure form of the diethanolamine salt of the compound of Formula I.(e.g., about 90% or greater chemical purity, about 95% or greaterchemical purity, or about 97.5% or greater chemical purity). Somemethods further comprise the step of: xxviii) reacting the first pureform of the diethanolamine salt of the compound of Formula I with anacid to generate a second pure form of the compound of Formula I (e.g.,about 98% or greater chemical purity, about 98.5% or greater chemicalpurity, or about 99% or greater chemical purity). And, some methodsfurther comprise the step of: xxvb) converting the second pure form ofthe compound of Formula I to an alkali metal salt.

Another aspect of the present invention provides a compound of Formula21

wherein R¹ is C₁₋₆ alkyl and each R³ is independently C₁₋₆ alkyl orphenyl.

In some embodiments, R¹ is methyl, ethyl, propyl, iso-propyl, butyl,sec-butyl, or tert-butyl.

In other embodiments, the —OSi(R³)₃ group is selected from

In some embodiments, R¹ is methyl and the —OSi(R³)₃ group is

Another aspect of the present invention provides a compound of Formula1a

Another aspect of the present invention provides a compound of Formula 5

wherein each of R² is independently selected from a C₁₋₆ alkyl orphenyl.

Another aspect of the present invention provides a compound of Formula9a

wherein R¹ is C₁₋₆ alkyl.

Another aspect of the present invention provides a compound of Formula13

wherein R¹ is C₁₋₆ alkyl and each R² is independently selected from C₁₋₆alkyl or phenyl.

Another aspect of the present invention provides a method of purifying acompound of Formula 1

comprising the steps of: xxx) reacting a compound of Formula 1 with aderivatizing reagent to generate a precipitate that is substantiallyinsoluble in dichloromethane or mixture thereof (e.g., a mixturecomprising dicloromethane and an alkane (e.g., heptane) (e.g., a mixturecomprising dichloromethane and about 50% or more by volume heptane));xxxi) collecting the precipitate and refluxing the precipitate in asolvent comprising an alcohol to generate the compound of Formula 1having a chemical purity of about 98% or greater (e.g., about 98.5% orgreater, about 99% or greater, or about 99.5% or greater) and an e.e. ofabout 98% or greater (e.g., about 98.5% or greater, about 99% orgreater, or about 99.5% or greater); wherein the method excludes the useof any column chromatography (e.g., HPLC).

In some implementations, the derivitizing reagent comprises3,5-dinitrobenzoyl chloride and the alcohol comprises methanol.

Another aspect of the present invention provides a method of purifying acompound of Formula 9

comprising the steps of: xl) reacting a compound of Formula 9, whereinR¹ is C₁₋₆ alkyl, with 3,5-dinitrobenzoyl chloride to generate aprecipitate comprising a compound of Formula 9A; and

xli) collecting the precipitate and treating the precipitate with a basein the presence of an alcohol to generate the compound of Formula 9having a chemical purity of about 95% or greater (e.g., about 98% orgreater, about 99% or greater, or about 99.5% or greater); wherein themethod excludes the use of any column chromatography (e.g., HPLC).

Some methods further comprise the step of: xlii) recrystallizing theprecipitate of step xli).

Another aspect of the present invention provides a method of generatinga compound of Formula 5

wherein each of R² is independently selected from a C₁₋₆ alkyl orphenyl, comprising the steps of:

-   iv) refluxing the compound of Formula 1a in the presence of methanol    to generate a compound of Formula 1 having an e.e. of greater than    about 98%;

v) reacting the compound of Formula 1 with SiCl(R²)₃, wherein each R² isindependently C₁₋₆ alkyl or phenyl, under basic conditions to generatethe compound of Formula 2;

vi) reacting the compound of Formula 2 with 1-TMS-1-propyne to generatethe compound of Formula 3;

l) deprotecting the compound Formula 3 under basic condition to generatea compound of Formula 4, wherein each of R⁴ and R⁵ are H or —OSi(R²)₃;and

li) reacting the compound of Formula 4 with SiCl(R²)₃ under basicconditions to generate the compound of formula 5, wherein the compoundof Formula 5 has a chemical purity of about 98% or greater (e.g., about98.5% or greater, about 99% or greater, or about 99.5% or greater) andan e.e. of about 98% or greater (e.g., about 98.5% or greater, about 99%or greater, or about 99.5% or greater).

Steps iv)-vi) are discussed above.

Another aspect of the present invention provides a method of generatinga compound of Formula 13

wherein R¹ is C₁₋₆ alkyl and each R² is independently selected from C₁₋₆alkyl or phenyl, comprising the step of: x) reacting a compound ofFormula 12 with(R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole inthe presence of an organic solvent comprising THF and toluene togenerate a compound of Formula 13

wherein the compound of Formula 13 has a chemical purity of greater thanabout 97% (e.g., about 97.5% or greater, about 98% or greater) and ad.e. of greater than about 97% (e.g., about 97.5% or greater, about 98%or greater, or about 98.5% or greater).

Step x) is described in detail above.

IV. GENERAL SYNTHETIC SCHEME

General schemes for generating compounds of Formula I and salts thereofare provided below.

In the general schemes above, R¹, R², and R³ are as defined above.

Some methods of the present invention comprise one or more of thefollowing reaction conditions:

-   -   Step xxx): 1. 3,5-dinitrobenzoyl chloride, DMAP, NEt₃, CH₂Cl₂,        0° C. to rt        -   2. recrystallization    -   Step iv): MeOH, reflux    -   Step v): TBSCl, imidazole, DMF, 0° C.    -   Step vi): 1-TMS-1-propyne, sec-BuLi, CuI, MTBE, −78° C.    -   Step l): KOH, EtOH    -   Step li): TBSCl, imidazole, DMF, 0° C.    -   Step xxii): 3-bromoprop-1-ene, sec-BuLi, Heptanes, 0° C.    -   Step xxiii): 1N aq. HCl, MeOH    -   Step xl): 1. 3,5-dinitrobenzoyl chloride, DMAP, NEt₃, CH₂Cl₂,        0° C. to r.t.        -   2. recrystallization    -   Step xli): KOH, MeOH    -   Step i): MnO₂, CH₂Cl₂    -   Step ii): compound of Formula 5, sec-BuLi, THF, −78° C. to r.t.    -   Step viii): MnO₂, CH₂Cl₂    -   Step x):        (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole,        BH₃, DMS, toluene/THF    -   Step a): TBSCl, imidazole, DMF, 0° C.    -   Step b): 1. CO₂(CO)₈, CH₂Cl₂, rt        -   2. CH₃CN, reflux    -   Step xii): H₂, 10% Pd/C, K₂CO₃, MeOH or THF    -   Step xix): NaBH₄, aq. NaOH, EtOH, −10° C.    -   Step xx): TBDPSCl, imidazole, DMF, 50° C.    -   Step xxi): Aq. HCl, THF/MeOH or TBAF, THF, 0° C.    -   Step xvii): triisopropylbenzene-sulfonyl chloride, Et₃N, DMAP,        CH₂Cl₂, 0° C. to r.t.    -   Step xviii): K₂CO₃, MeOH    -   Step xv): nBuLi, CuI, THF, −78° C. to r.t.    -   Step c): Ph₂PH, nBuLi, THF, −20° C. to reflux    -   Step d): TBAF, THF, 50° C.    -   Step e): R² substituted 2-bromoacetate, K₂CO₃, KI, acetone    -   Step f): KOH, MeOH    -   Step xxiv): diethanolamine, EtOAc, EtOH, reflux to r.t.    -   Step xxva): NaOH, EtOH    -   Step xxvb): NaOH, EtOH    -   Step xxvi): NaOH, H₂O, MeOH    -   Step xxvii): 3N aq. HCl, H₂O

VI. Alternative Steps

The present invention also provides the following synthetic steps,wherein one or more of the following steps may be optionally substitutedfor one or more steps described above.

Step A1):

Step A2):

Steps A3) and A4):

Steps A5)-A7):

Steps A8)-A11):

Steps A12)-A23):

Steps A24)-A30):

Steps A31) and A32)

Steps A33)-A36)

Steps A37) and A38)

VII. EXAMPLES

The following examples are not intended to limit the scope of thepresent invention.

Example 1 (R)-oxiran-2-ylmethyl 3,5-dinitrobenzoate (1a)

Triethylamine (8.52 g/mL, 84.2 mmol, 1.25 equiv) and4-dimethylaminopyridine (100 mg, 0.818 mmol, 0.01 equiv) were added to asolution of (S)-(−)-glycidol 1 (5.00 g, 67.5 mmol, 1.0 equiv, 99.5% ee)in anhydrous methylene chloride (100 mL) while stirring under nitrogen.The reaction was then warmed to 30° C. and 3,5-dinitrobenzoyl chloride(16.3 g, 70.9 mmol, 1.05 equiv) added drop-wise over 20 minutes as asolution in anhydrous methylene chloride (50 mL). After stirring at thistemperature for 30 minutes, the reaction was quenched with addition of10% aqueous potassium bicarbonate (50 mL) and cooled to room temperaturewhile stirring for an additional 30 minutes. The two phases wereseparated and the organic phase washed with 10% aqueous citric acid (50mL). The organic phase was then purified by filtration through a plug ofsilica gel giving 14.69 g of a white solid that was shown to be 99.4%e.e. by chiral HPLC. Recrystallization (180 mL of 3:2 v/vheptane-dichloromethane) afforded 11.5 g (64%) of the title compound asa white solid. Data for 1a: R_(f)=0.43 (100% methylene chloride); ¹H NMR(400 MHz, CDCl₃) δ 9.25-9.28 (m, 1H), 9.21 (d, J=2.20 Hz, 2H), 4.82 (dd,J=2.93, 12.45 Hz, 1H), 4.20-4.33 (m, 1H), 3.42 (tdd, J=2.61, 4.07, 6.82Hz, 1H), 2.92-3.04 (m, 1H), 2.77 (dd, J=2.75, 4.58 Hz, 1H); MS (ESI+)m/z 291.0 (M+Na⁺). HPLC, ChiralPak IA column (4.6×250 mm²), 5 mm; flowrate 1.0 mL/min; 210 nm; mobile phase heptane (80%): ethanol (20%);retention time, 27.0 min, purity (100.0%).

Example 2 (S)-(−)-glycidol (1, ˜100% ee)

A solution of dinitrobenzoate 1a (30.06 g, 112.1 mmol, 1.0 equiv) inanhydrous methanol (190 mL) was heated to reflux for 2 hours whilestirring, under nitrogen. The reaction was then cooled to 0° C. in anice bath causing formation of a crystalline solid that was removed byfiltration and rinsed with ice cold methanol (15 mL). The filtrate wasconcentrated under reduced pressure resulting in formation of a whiteslurry that was dissolved in tert-butyl methyl ether (20 mL) andconcentrated to dryness. The residue was again slurried in methanol (15mL), the solid removed by filtration and rinsed with more methanol (5mL). The filtrate was concentrated to give 7.6 g (92%) of the titlecompound as a pale yellow oil. Data for 1: R_(f)=0.12 (20%EtOAc/heptane).

Example 3 (R)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane (2a)

To a 0° C. solution of tert-butyl(chloro)dimethylsilane (26.540 g,176.21 mmol, 1.3 equiv) and imidazole (14.786 g, 217.19 mmol, 1.6 equiv)in dimethylformamide (80 mL) was added (S)-oxiran-2-yl methanol (10.013g, 135.16 mmol, 1.0 equiv) drop-wise and the resulting mixture stirredat that temperature under nitrogen for 30 minutes. The reaction was thenquenched with addition of saturated aqueous ammonium chloride (200 mL)and water (200 mL). The resulting mixture was extracted with heptane(5×200 mL) and the combined organic phases were washed with brine, dried(MgSO₄) and concentrated to give 25.142 g (99%) of the title compound asa yellow oil. This material was used in the next step withoutpurification. Data for 2a: R_(f)=0.64 (20% EtOAc/heptane); ¹H NMR (400MHz, CDCl₃) δ 3.85 (dd, J=3.22, 12.01 Hz, 1H), 3.66 (dd, J=4.69, 12.01Hz, 1H), 3.05-3.12 (m, 1H), 2.76 (dd, J=4.25, 5.13 Hz, 1H), 2.63 (dd,J=2.64, 4.98 Hz, 1H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).

Example 4(R)-1-((tert-butyldimethylsilyl)oxy)-6-(trimethylsilyl)hex-5-yn-2-ol(3a)

To a 3-neck flask fitted with a mechanical stirrer, a thermocouple andaddition funnel was charged 1-(trimethylsilyl)-1-propyne (120.0 g, 1.07mol, 2.2 equiv) followed by tert-butyl methyl ether (600 mL) while beingkept under nitrogen. The solution was cooled to 0±5° C. while stirringand sec-butyllithium (696 mL, mmol, 2.0 equiv, 2 M in cyclohexane) wasadded slowly while maintaining the reaction temperature below 5° C.After complete addition, the resulting mixture was stirred at 0±5° C.under nitrogen for three hours. In a separate 3-neck flask fitted with amechanical stirrer, a thermocouple, and addition funnel was chargedepoxide 2a (92.5 g, 0.49 mol, 1.0 equiv) followed by tert-butyl methylether (1800 mL) and copper iodide (18.6 g, 0.1 mol, 0.2 equiv) whilebeing kept under nitrogen. The resulting mixture was cooled to −78°C.±5° C. and then the 1-(trimethylsilyl)-1-propyne solution wascannulated into the epoxide reaction mixture. The resulting reactionmixture was allowed to slowly warm to room temperature. After stirringfor 18 hours, the reaction was judged complete by TLC. The reaction wasquenched with addition of 5% aqueous citric acid (1500 mL), the layerswere separated and the lower aqueous layer was extracted with heptane(1000 mL). The combined organic phases were filtered through a pad ofcelite (150 g) and the filtrate was concentrated under reduced pressureto give 147 g (˜100%) of the title compound as a dark yellow/brown oil.This material was used in the next step without purification. Data for3a: R_(f)=0.55 (20% EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 3.72-3.82(m, 1H), 3.65 (dd, J=3.81, 9.96 Hz, 1H), 3.45 (dd, J=7.03, 9.96 Hz, 1H),2.47 (d, J=3.81 Hz, 1H), 2.34-2.42 (m, 2H), 1.63 (q, J=7.13 Hz, 2H),0.91 (s, 9H), 0.14 (s, 9H), 0.08 (s, 6H); MS (ESI+) m/z 324.4 (M+Na⁺).

Example 5 (R)-1-((tert-butyldimethylsilyl)oxy)hex-5-yn-2-ol (4a)

To a 3-neck flask fitted with a mechanical stirrer and thermocouple wascharged(R)-1-((tert-butyldimethylsilyl)oxy)-6-(trimethylsilyl)hex-5-yn-2-ol 3a(147 g, 489 mmol, 1 equiv) dissolved in ethanol (1200 mL) undernitrogen. Solid potassium hydroxide pellets (55 g, 980 mmol, 2.0 equiv)was added and the resulting solution was stirred at room temperature for2 hours. After completion of the reaction as judged by TLC, the reactionmixture was concentrated under reduced pressure. The crude residue wastreated with heptane (1000 mL) and 10% citric acid solution (1700 mL)and the resulting mixture was stirred for 5 minutes. The layers wereseparated and the lower aqueous layer was extracted with heptane (700mL). The combined organic phases were filtered through a pad of celite(120 g) and concentrated under reduced pressure to give 85 g (77%) ofthe title compound as a light brown oil. This material was anunquantified mixture of regioisomers due to migration of the silylprotecting group that was used in the next step without furtherpurification. Purification of a small amount of crude 4a bychromatography (0% to 25% ethyl acetate/heptane gradient) providedanalytically pure samples of 4b and 4c. Data for 4b: R_(f)=0.50 (20%EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 3.73-3.84 (m, 1H), 3.60-3.68(m, 1H), 3.44 (dd, J=7.14, 10.07 Hz, 1H), 2.45 (br. s., 1H), 2.35 (dt,J=2.56, 7.14 Hz, 2H), 1.95 (t, J=2.56 Hz, 1H), 1.59-1.67 (m, 2H), 0.90(s, 9H), 0.07 (s, 6H); MS (ESI+) m/z 229.2 (M+H⁺). Data for 4c:R_(f)=0.40 (20% EtOAc/heptane); ¹H NMR (400 MHz, CHLOROFORM-d) δ3.84-3.97 (m, 1H), 3.56-3.66 (m, 1H), 3.43-3.54 (m, 1H), 2.25 (dt,J=2.56, 7.14 Hz, 2H), 1.96 (t, J=2.75 Hz, 1H), 1.89 (br. s., 1H),1.65-1.81 (m, 2H), 0.78-0.98 (m, 9H), 0.12 (s, 3H), 0.10 (s, 3H); MS(ESI+) m/z 229.2 (M+H⁺).

Example 6(R)-5-(but-3-yn-1-yl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane(5a)

To a 3-neck flask fitted with a mechanical stirrer, a thermocouple andaddition funnel was charged tert-butyldimethylsilyl chloride (59.0 g,391 mmol, 1.05 equiv) and imidazole (40.5 g, 595 mmol, 1.6 equiv) indimethylformamide (1100 mL). The solution was cooled to 0±5° C. whilestirring. Then, a solution of(R)-1-((tert-butyldimethylsilyl)oxy)hex-5-yn-2-ol 4a (85 g, 372 mmol,1.0 equiv) dissolved in dimethylformamide (200 mL) and added slowly tothe reaction while maintaining the temperature below 5° C. Upon completeaddition, the resulting mixture was stirred at 0±5° C. under nitrogenfor three hours and then was slowly warmed up to room temperature andstir under nitrogen for at least 15 hrs. The reaction mixture was thendiluted with methyl tert-butyl ether (1500 mL) and quenched with 5%aqueous citric acid (1500 mL). The layers were separated and the loweraqueous layer was extracted with methyl tert-butyl ether (3×1000 mL).The combined organic phases were washed with 14% aqueous sodiumchloride, and concentrated under reduced pressure to give an orange oil.Chromatography (1% to 10% ethyl acetate/heptane gradient) afforded 114 g(90%) of the title compound as a yellow oil. Data for 5a: R_(f)=0.89(20% EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 3.72-3.84 (m, 1H), 3.56(dd, J=5.13, 10.25 Hz, 1H), 3.41 (dd, J=6.59, 9.89 Hz, 1H), 2.19-2.35(m, 2H), 1.90-1.95 (m, 1H), 1.75-1.89 (m, 1H), 1.54-1.66 (m, 1H), 0.90(s, 9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 6H); MS(ESI+) m/z 343.2 (M+H⁺). Chiral GC, Restek bDEXm column (30 m×0.32 mm),65° C. for 40 min, 10° C./min to 130° C., 20° C./min to 200° C., 1 mLinjection; retention time, 43.49 min (˜100% 5a); Chemical Purity GC,Restek Stabilwax column (30 m×0.32 mm), 60° C. for 2 min, 10° C./min to230° C., 1 mL injection; retention time, 10.82 min (90.0% 5a).

Example 7 tert-butyl((3-methoxybenzyl)oxy)dimethylsilane (7b)

To a solution of 3-methoxybenzyl alcohol 6 (2500 g, 18.09 mol, 1.0equiv) in dichloromethane (20 L, 8 volumes) was added imidazole (1466 g,21.53 mol, 1.19 equiv) and the solution cooled to 15° C. while stirringunder nitrogen. Once cooled, the solution was charged withtert-butyl(chloro)dimethyl-silane (3164 g, 20.99 mol, 1.16 equiv) overthe next 9 minutes during which time an exotherm of 42.9° C. wasobserved. The reaction was then cooled to room temperature whilestirring for 17 hours. The reaction was then quenched with 5% aqueouscitric acid (20 L, 8 volumes) and the lower organic phase concentratedto give 4958 g of a pale yellow oil. Vacuum distillation done in twobatches (bp ranges 115-120° C., 132-135° C. at 5 torr) afforded 2336 gand 1964 g of a clear colorless oil, which totaled 4300 g (94%) of thetitle compound. Data for 7b: R_(f)=0.27 (1% EtOAc/heptane); ¹H NMR (400MHz, CDCl₃) δ 7.25 (t, J=8.1 Hz, 1H), 6.91 (m, 1H), 6.79 (dd, J=2.4, 8.2Hz, 2H), 4.74 (s, 2H), 3.82 (s, 3H), 0.96 (s, 9H), 0.11 (s, 6H); MS(ESI+) m/z 275.2 (M+Na⁺).

Example 8 ((2-allyl-3-methoxybenzyl)oxy)(tert-butyl)dimethylsilane (8b)

A solution of silane 7b (2660 g, 10.54 mol, 1.0 equiv) in heptane (13.30L, 5 volumes) was treated drop-wise with sec-butyllithium (15.81 L,22.13 mol, 2.1 equiv, 1.4 M in cyclohexane) over a period of 2 hours.The reaction was stirred at room temperature for 2 additional hoursbefore cooling to 0° C. Once cooled, the reaction was treated drop-wisewith allyl bromide (2805 g, 23.18 mol, 2.2 equiv) over the next 70minutes. An exotherm of 17.6° C. was observed, and the reaction warmedto room temperature over the next 38 minutes. The reaction was stirredat room temperature for 20 hours and was then quenched with 20% aqueousammonium chloride (13.30 L, 5 volumes). The organic phase was washedwith 14% aqueous sodium chloride (5.32 L, 2 volumes) and wasconcentrated to give 3274 g of yellow oil. This material was deemedsufficiently pure to be carried forward. Data for 8b: R_(f)=0.64 (5%EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 7.22 (t, J=8.1 Hz, 1H), 7.11(d, J=7.7 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 5.92 (m, 1H), 4.93 (m, 2H),4.74 (s, 2H), 3.82 (s, 3H), 3.41 (dt, J=1.6, 6.0 Hz, 2H), 0.95 (s, 9H),0.10 (s, 6H); MS (ESI+) m/z 315.2 (M+Na⁺).

Example 9 (2-allyl-3-methoxyphenyl)methanol (9b)

To a solution of silane 8b (3082 g, 10.54 mol, 1.0 equiv, theoreticalweight) in methanol (30.82 L, 10 volumes) was added 6N aqueoushydrochloric acid (8.43 L, 8.431 mol, 0.8 equiv) and the reactionstirred at room temperature for 2 hours. The reaction was quenched withdrop-wise addition of 10% aqueous potassium bicarbonate (15.41 L,5volumes) and then evaporated until approximately 10 volumes of methanolwere removed. The resulting aqueous solution was extracted with ethylacetate (15.41 L, 10 volumes). The combined organic phases were washedwith 7% sodium chloride (15.41 L, 5 volumes) and concentrated to give2582 g of a brown oil. Vacuum distillation (bp range 132-135° C. at 5torr) afforded 1558 g (83%, 2 steps) of the title compound as a yellowoil. This material was deemed sufficiently pure to be carried forward.Data for 9b: R_(f)=0.36 (30% EtOAc/heptane);); ¹H NMR (400 MHz, CDCl₃) δ7.24 (t, J=8.1 Hz, 1H), 7.03 (d, J=7.7 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H),6.01 (m, 1H), 4.97 (dq, J=1.8, 10.0 Hz, 1H), 4.92 (dq, J=1.9, 17.1 Hz,1H), 4.70 (s, 2H), 3.84 (s, 3H), 3.52 (dt, J=1.7, 5.9 Hz, 2H); MS (ESI+)m/z 201.1 (M+Na⁺).

Example 10 2-allyl-3-methoxybenzyl 3,5-dinitrobenzoate (9c)

To a 0° C. solution of alcohol 9b (1558 g, 11.28 mol, 1.0 equiv) indichloromethane (7.789 L, 5 volumes) was added 3,5-dinitrobenzoylchloride (2860 g, 12.40 mol, 1.1 equiv) and 4-dimethylamino-pyridine(206.6 g, 1.690 mol, 0.15 equiv) resulting in an exotherm of 12.6° C.The reaction was cooled back to 0° C. and triethylamine (1.729 L, 12.40mol, 1.1 equiv) was added drop-wise over the next 57 minutes, duringwhich time an exotherm of 17.6° C. was observed. Upon completion of thetriethylamine addition, the reaction was quenched with 10% aqueouspotassium bicarbonate (7.789 L, 5 volumes) which generated an exothermof 19.8° C. The lower organic layer was washed with 10% aqueous citricacid (7.789 L, 5 volumes) and concentrated to give 4118 g of a lightbrown amorphous solid. The crude solid was suspended in methanol (41.18L, 10 volumes based on crude quantity) and was heated to 65° C. over 94minutes to fully dissolve the solid. The solution was then cooled backto room temperature and the precipitated solid was isolated byfiltration. The solid was vacuum dried at 40° C. for 20 hours to afford2131 g (65%) of the title compound as a light yellow solid. Thismaterial was deemed sufficiently pure to be carried forward. Data for9c: R_(f)=0.45 (30% EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 9.22 (t,J=2.2 Hz, 1H), 9.16 (d, J=2.2 Hz, 2H), 7.28 (t, J=8.1 Hz, 1H), 7.08 (dd,J=0.9, 7.5 Hz, 1H), 6.97 (d, J=8.1 Hz, 1H), 5.99 (ddt, J=5.8, 10.1, 17.2Hz, 1H), 5.49 (s, 2H), 4.98 (dq, J=1.8, 17.2 Hz, 1H), 4.89 (dq, J=1.7,10.1 Hz, 1H), 3.87 (s, 3H), 3.57 (dt, J=1.8, 5.9 Hz, 2H); MS (ESI+) m/z395.1 (M+Na⁺).

Example 11 (2-allyl-3-methoxyphenyl)methanol (9b)

To a slurry of dinitrobenzoate 9c (3463 g, 9.302 mol, 1.0 equiv) inmethanol (17.32 L, 5 volumes) was added potassium hydroxide (719.9 g,11.16 mol, 1.2 equiv) and water (3.463 L, 1 volume), generating anexotherm of 37.7° C. The reaction was cooled to room temperature whilestirring over 1 hour and was then concentrated until 5 volumes ofmethanol was removed. The resulting slurry was dissolved in 10% aqueouscitric acid (17.32 L, 5 volumes) and extracted with dichloromethane(17.32 L, 5 volumes). The solid dinitrobenzoic acid byproduct wasremoved by filtration and the filtrate was washed with 10% aqueouspotassium carbonate (9.02 L, 5 volumes) and concentrated to afford 1464g (88%) of the title compound as a dark green oil. This material wasdeemed sufficiently pure to be carried forward. Data for 9b: R_(f)=0.36(30% EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 7.24 (t, J=8.1 Hz, 1H),7.03 (d, J=7.3 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.01 (m, 1H), 4.96 (m,2H), 4.70 (s, 2H), 3.84 (s, 3H), 3.52 (dt, J=1.6, 6.0 Hz, 2H); MS (ESI+)m/z 201.1 (M+Na⁺).

Example 12 2-Allyl-3-Methoxybenzaldehyde (10b)

Manganese (IV) oxide (85.00 g, 977.6 mmol, 10.0 equiv) was added to asolution of alcohol 9b (17.424 g, 97.761 mmol, 1.0 equiv) in anhydrousmethylene chloride (5 mL) and the mixture stirred under nitrogen for 16hours. The reaction was then filtered through celite, the solids washedwith heptane and the filtrate concentrated to give 534 mg (99%) of thetitle compound as a pale oil. Data for 10b: R_(f)=0.64 (30%EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 10.28 (s, 1H), 7.49 (dd,J=1.1, 7.7 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.13 (dd, J=0.9, 8.2 Hz,1H), 6.02 (ddt, J=5.9, 10.0, 17.1 Hz, 1H), 5.02 (dq, J=1.6, 10.1, 5.0Hz, 1H), 4.93 (dq, J=1.7, 17.2, 4.9 Hz, 1H), 3.88 (s, 3H), 3.86 (dt, 5.9Hz, 2H); MS (ESI+) m/z 199.1 (M+Na⁺).

Example 13(6R)-1-(2-allyl-3-methoxyphenyl)-6,7-bis((tert-butyldimethylsilyl)oxy)hept-2-yn-1-ol(11c)

A solution of alkyne 5a (1.070 g, 3.121 mmol, 1.1 equiv) in anhydrousMTBE (11 mL) that had been cooled to −78° C. was treated drop-wise withsec-butyllithium (2.20 mL, 3.12 mmol, 1.1 equiv, 1.4 M solution incyclohexane) and the resulting mixture stirred at that temperature undernitrogen for 30 minutes. Then, aldehyde 10b (500 mg, 2.83 mmol, 1.0equiv) was added drop-wise as a solution in MTBE (4 mL) and the reactionallowed to slowly warm to room temperature. After stirring for 17 hours,the reaction was quenched with addition of 10% aqueous citric acid (30mL) and extracted with heptane (3×30 mL). The combined organic phaseswere then washed with brine and concentrated to give 1.6 g of a yellowoil. Chromatography (0% to 15% ethyl acetate/heptane gradient) afforded1.340 g (91%) of the title compound as a pale yellow oil. Data for 11c:R_(f)=0.60 (20% EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 7.35 (d,J=7.91 Hz, 1H), 7.19-7.29 (m, 1H), 6.87 (dd, J=0.88, 8.20 Hz, 1H),5.93-6.08 (m, 1H), 5.64 (s, 1H), 4.90-5.03 (m, 2H), 3.83 (s, 3H),3.71-3.80 (m, 1H), 3.60-3.70 (m, 1H), 3.50-3.60 (m, 2H), 3.40 (dd,J=6.74, 9.96 Hz, 1H), 2.25-2.44 (m, 2H), 2.04 (br. s., 1H), 1.76-1.90(m, 1H), 1.60 (dtd, J=6.30, 7.67, 13.81 Hz, 1H), 0.90 (s, 9H), 0.88 (s,9H), 0.05 (s, 12H); MS (ESI+) m/z 541.4 (M+Na⁺).

Example 14(R)-1-(2-allyl-3-methoxyphenyl)-6,7-bis((tert-butyldimethylsilyl)oxy)hept-2-yn-1-one(12b)

Manganese (IV) oxide (869 mg, 10.0 mmol, 10.0 equiv) was added to asolution of alcohol 11c (540 mg, 1.04 mmol, 1.0 equiv) in anhydrousmethylene chloride (5 mL) and the mixture stirred under nitrogen for 16hours. The reaction was then filtered through celite, the solids washedwith heptane and the filtrate concentrated to give 534 mg (99%) of thetitle compound as a pale oil. Data for 12b: R_(f)=0.62 (normal phase,20% EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 7.74 (dd, J=1.17, 7.81 Hz,1H), 7.24-7.35 (m, 1H), 7.07 (dd, J=0.78, 8.20 Hz, 1H), 5.90-6.06 (m,1H), 4.86-5.09 (m, 2H), 3.86 (s, 3H), 3.75-3.84 (m, 3H), 3.58 (dd,J=5.27, 9.96 Hz, 1H), 3.41 (dd, J=6.84, 9.96 Hz, 1H), 2.44-2.66 (m, 2H),1.87-2.01 (m, 1H), 1.72 (dtd, J=5.86, 7.81, 13.67 Hz, 1H), 0.90 (s, 9H),0.89 (s, 9H), 0.08 (s, 6H), 0.06 (s, 6H); MS (ESI+) m/z 517.2 (M+H⁺).

Example 15(1S,6R)-1-(2-allyl-3-methoxyphenyl)-6,7-bis((tert-butyldimethylsilyl)oxy)hept-2-yn-1-ol(13c)

Aryl ketone 12b (95.7 g, 185 mmol, 1.0 equiv) was dissolved in THF (1900mL) under nitrogen. (R)-(+)-2-methyl-CBS-oxazaborolidine (222 mL, 222mmol, 1.2 equiv, 1 M solution in toluene) was added and the resultingmixture cooled to −50° C.±5° C. Borane-methyl sulfide complex (370 mL,370 mmol, 4.0 equiv, 2.0 M solution in THF) was then added drop-wiseover 20 minutes. After stirring at −50° C. for 75 minutes, the mixturewas cautiously quenched with drop-wise addition of methanol (600 mL) andsubsequently warmed to room temperature while stirring overnight. Thequenched mixture was cooled to 0° C., diluted with ethyl acetate (2000mL) and treated with 5% aqueous citric acid (1500 mL). The layers wereseparated and the aqueous phase was further extracted with ethyl acetate(2×1500 mL). The combined organic phases were washed with 14% sodiumchloride solution (1500 mL) and concentrated under reduced pressure. Thecrude oil was chased with heptane (2×500 mL) to afford 96.35 g of a paleoil. This material was deemed sufficiently pure to be carried forwardcrude. Data for 13c: R_(f)=0.58 (20% EtOAc/heptane); ¹H NMR (400 MHz,CDCl₃) d 7.35 (dd, J=1.03, 7.76 Hz, 1H), 7.20-7.29 (m, 1H), 6.87 (dd,J=0.88, 8.20 Hz, 1H), 6.00 (tdd, J=5.64, 10.18, 17.21 Hz, 1H), 5.63 (br.s., 1H), 4.87-5.06 (m, 2H), 3.83 (s, 3H), 3.75 (dddd, J=4.25, 5.27,6.66, 7.84 Hz, 1H), 3.61-3.69 (m, 1H), 3.51-3.61 (m, 2H), 3.40 (dd,J=6.74, 9.96 Hz, 1H), 2.26-2.42 (m, 2H), 2.06 (br. s., 1H), 1.78-1.90(m, 1H), 1.60 (dtd, J=5.86, 7.95, 13.70 Hz, 1H), 0.90 (s, 9H), 0.88 (s,9H), 0.05 (s, 12H); MS (ESI+) m/z 541.2 (M+Na+); HPLC, ChiralPak IAcolumn (4.6×250 mm2), 5 mm; flow rate 1.0 mL/min; 210 nm; mobile phaseheptane (99%): 2-propanol (1%): trifluoroacetic acid (0.1%); retentiontime, 8.66 min (1.2%,(1R,6R)-1-(2-allyl-3-methoxyphenyl)-6,7-bis((tert-butyldimethylsilyl)oxy)hept-2-yn-1-ol),retention time, 9.48 min (98.8%, 13c).

Example 16(5S,10R)-5-(2-allyl-3-methoxyphenyl)-10-((tert-butyldimethylsilyl)oxy)-2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-3,13-disilapentadec-6-yne(14c)

Imidazole (1.732 g, 25.44 mmol, 1.2 equiv) andtert-butyl(chloro)dimethylsilane (3.545 g, 23.32 mmol, 1.1 equiv) wereadded to a stirred, 0° C. solution of alkynol 13c (11.002 g, 21.20 mmol,1.0 equiv) in anhydrous DMF under nitrogen and the mixture was thenwarmed to room temperature. The reaction was then quenched with additionof saturated aqueous ammonium chloride (100 mL) and water (100 mL). Theresulting mixture was extracted with heptane (3×200 mL) and the combinedorganic phases were washed with water, brine, dried (MgSO₄) andconcentrated to give 13.351 g (99%) of the title compound as a paleyellow oil. This material was deemed sufficiently pure to be carriedforward. Data for 14c: R_(f)=0.82 (20% EtOAc/heptane); ¹H NMR (400 MHz,CDCL₃) δ 7.25-7.32 (m, 1H), 7.18-7.25 (m, 1H), 6.82 (d, J=8.20 Hz, 1H),5.88-6.04 (m, 1H), 5.58 (s, 1H), 4.88-5.03 (m, 2H), 3.82 (s, 3H),3.67-3.76 (m, 1H), 3.57-3.66 (m, 1H), 3.46-3.57 (m, 2H), 3.37 (dd,J=6.45, 9.96 Hz, 1H), 2.16-2.34 (m, 2H), 1.70-1.85 (m, 1H), 1.47-1.60(m, 1H), 0.91 (s, 9H), 0.89 (s, 9H), 0.87 (s, 9H), 0.12 (s, 3H), 0.09(s, 3H), 0.04 (s, 12H); MS (ESI+) m/z 655.5 (M+Na⁺).

Example 17(4R,9aS)-3-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-4-((tert-butyldimethylsilyl)oxy)-8-methoxy-9,9a-dihydro-1H-cyclopenta[b]naphthalen-2(4H)-one(15d)

Cobalt carbonyl (7.197 g, 21.05 mmol, 1.0 equiv) was added to a solutionof compound 14c (13.326 g, 21.05 mmol, 1.0 equiv) in anhydrous methylenechloride and the reaction stirred at room temperature under nitrogen for2 hours to allow for formation of the cobalt-alkyne complex. Thereaction was then concentrated by rotary evaporation, the residuedissolved in anhydrous acetonitrile and the mixture heated to refluxwith stirring for 18 hours. The reaction was then cooled to roomtemperature, filtered through celite, and the precipitate washed withseveral portions of acetone. The filtrate was concentrated to give 14.9g of an amber oil. Chromatography (0% to 20% ethyl acetate/heptanegradient) afforded 13.803 g (99%) of the title compound as a colorlessoil. Data for 15d: R_(f)=0.57 (20% EtOAc/heptane); ¹H NMR (400 MHz,CDCl₃) δ 7.24 (t, J=7.91 Hz, 1H), 6.91 (d, J=7.62 Hz, 1H), 6.79 (d,J=7.91 Hz, 1H), 5.51 (s, 1H), 3.83 (s, 3H), 3.61-3.71 (m, 1H), 3.30-3.59(m, 4H), 2.70 (dd, J=6.45, 18.75 Hz, 1H), 2.35-2.48 (m, 1H), 2.10-2.32(m, 3H), 1.57 (td, J=7.58, 15.01 Hz, 2H), 0.91 (s, 9H), 0.88 (s, 9H),0.82 (s, 9H), 0.00-0.14 (m, 18H); MS (ESI+) m/z 683.4 (M+Na⁺).

Example 18a(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one(16d)

To a solution of tricyclic enone 15d (14.86 g, 22.48 mmol, 1.0 equiv) inabsolute methanol (225 mL) was added anhydrous potassium bicarbonate(743 mg, 5% w/w) and 10% Pd/C (3.715 g, 50% wet, 25% w/w) and themixture was hydrogenated with a balloon of hydrogen gas while stirringat room temperature for 64 hours. The reaction mixture was then filteredthrough celite, the residue washed with several portions of ethanol, andthe filtrate concentrated to give a yellow oil. Triteration with heptanecaused formation of a small amount of precipitate that was filtered off,and the filtrate concentrated to give 12.5 g of a viscous, yellow oil.Chromatography (0% to 10% ethyl acetate/heptane gradient) afforded10.998 g (92%) of the title compound as a pale oil. Data for 16d:R_(f)=0.47 (20% EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 7.11 (t,J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz, 2H), 3.84 (s, 3H), 3.62-3.76 (m,1H), 3.52-3.61 (m, 1H), 3.43 (dd, J=6.84, 9.96 Hz, 1H), 2.10-3.08 (m,8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz, 18H), 0.01-0.18 (m, 12H); MS(ESI+) m/z 533.2 (M+H⁺).

Example 18b(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one(16d)

To a solution of tricyclic enone 15d (1.0 g, mmol, 1.0 equiv) inmethanol (10 mL) was added anhydrous potassium carbonate (53 mg, 5% w/w)and 10% Pd/C (100 mg, 50% wet, 10% w/w) and the mixture was hydrogenatedunder 10 psi hydrogen gas while stirring at room temperature for about18 hours. The reaction mixture was then filtered through celite, theresidue was washed with several portions of MTBE, and the filtrateconcentrated to give a yellow oil. Triteration with MTBE causedformation of a small amount of precipitate that was filtered off, andthe filtrate concentrated to give 0.98 g of viscous, yellow oil. Thismaterial was deemed sufficiently pure to be carried forward, but waspurified for analytical characterization. Chromatography (0% to 2.5%ethyl acetate/heptane) afforded 0.711 g (88%) of the title compound as aviscous, colorless oil. Data for 16d: R_(f)=0.64 (20% EtOAc/heptane); ¹HNMR (400 MHz, CDCl₃) δ 7.11 (t, J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz, 2H),3.84 (s, 3H), 3.62-3.76 (m, 1H), 3.52-3.61 (m, 1H), 3.43 (dd, J=6.84,9.96 Hz, 1H), 2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz,18H), 0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2 (M+H⁺).

Example 18c(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one(16d)

To a solution of tricyclic enone 15d (500 mg, 0.756 mmol, 1.0 equiv) inethyl acetate (7.5 mL) was added anhydrous potassium carbonate (25 mg,5% w/w) and 10% Pd/C (75 mg, 50% wet, 15% w/w). The mixture washydrogenated under 10 psi hydrogen gas while shaking in a Parr flask atroom temperature for 24 hours. The reaction was then charged withadditional 10% Pd/C (75 mg, 50% wet, 15% w/w), and hydrogenated under 10psi hydrogen gas while shaking in a Parr flask at room temperature for24 more hours. At this point the reaction was shown to be complete byTLC and was filtered through celite, the residue was washed with severalportions of ethyl acetate, and the filtrate concentrated to give 404 mgof a light yellow oil. Chromatography (0% to 5% ethyl acetate/heptanegradient) afforded 290 mg (72%) of the title compound as a viscous,colorless oil. Data for 16d: R_(f)=0.47 (20% EtOAc/heptane); ¹H NMR (400MHz, CHLOROFORM-d) δ 7.11 (t, J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz, 2H),3.84 (s, 3H), 3.62-3.76 (m, 1H), 3.52-3.61 (m, 1H), 3.43 (dd, J=6.84,9.96 Hz, 1H), 2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz,18H), 0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2 (M+H⁺).

Example 18d(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one(16d)

To a solution of tricyclic enone 15d (1.000 g, 1.513 mmol, 1.0 equiv) in2-methyltetrahydrofuran (15 mL) was added anhydrous potassium carbonate(50 mg, 5% w/w) and 10% Pd/C (150 mg, 50% wet, 10% w/w) and the mixturewas hydrogenated under 10 psi hydrogen gas while stirring at roomtemperature for about 18 hours. The reaction was then charged withadditional 10% Pd/C (150 mg, 50% wet, 15% w/w), and hydrogenated under10 psi hydrogen gas while stirring at room temperature for about 23hours. At this point the reaction was shown to be complete by TLC andwas filtered through celite, the residue was washed with severalportions of ethyl acetate, and the filtrate concentrated to give 984 mgof a light yellow oil. Chromatography (0% to 5% ethyl acetate/heptanegradient) afforded 507 mg (63%) of the title compound as a viscous,colorless oil. Data for 16d: R_(f)=0.47 (20% EtOAc/heptane); ¹H NMR (400MHz, CHLOROFORM-d) δ 7.11 (t, J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz, 2H),3.84 (s, 3H), 3.62-3.76 (m, 1H), 3.52-3.61 (m, 1H), 3.43 (dd, J=6.84,9.96 Hz, 1H), 2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz,18H), 0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2 (M+H⁺).

Example 18e(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one(16d)

To a solution of tricyclic enone 15d (1.465 g, 2.216 mmol, 1.0 equiv) inabsolute ethanol (225 mL) was added anhydrous potassium carbonate (126mg, 8.5% w/w) and 10% Pd/C (225 mg, 50% wet, 15% w/w) and the mixturewas hydrogenated at atmospheric pressure of hydrogen gas while stirringat room temperature overnight. The reaction mixture was then filteredthrough celite, the residue washed with several portions of ethanol, andthe filtrate concentrated to give yellow oil. Triteration with heptanecaused formation of a small amount of precipitate that was filtered off,and the filtrate was concentrated to give a viscous, yellow oil. Thecrude oil was dissolved in ethanol (15 mL) and DI water (7 mL) was addedslowly to the stirred solution. The white solid was filtered and washedwith a 1:1 mixture of ethanol and DI water. The solid was dried undervacuum overnight to afford 985 mg (83%) of the title compound as a whitesolid. Data for 16d: Rf=0.47 (20% EtOAc/heptane); ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.11 (t, J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz, 2H), 3.84(s, 3H), 3.62-3.76 (m, 1H), 3.52-3.61 (m, 1H), 3.43 (dd, J=6.84, 9.96Hz, 1H), 2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz, 18H),0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2 (M+H⁺).

Example 18f(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one(16d)

To a solution of tricyclic enone 15d (1.425 g, 2.155 mmol, 1.0 equiv) inabsolute ethanol (225 mL) was added anhydrous potassium carbonate (116mg, 8% w/w) and 10% Pd/C (220 mg, 50% wet, 15% w/w) and the mixture washydrogenated under 10 psi of hydrogen gas while stirring at roomtemperature overnight. The reaction mixture was then filtered throughcelite, the residue washed with several portions of ethanol, and thefiltrate concentrated to give a yellow oil. Triteration with heptanecaused formation of a small amount of precipitate that was filtered off,and the filtrate was concentrated to give a viscous, yellow oil. Thecrude oil was dissolved in ethanol (15 mL) and DI water (7 mL) was addedslowly to the stirred solution. The white solid was filtered and washedwith a 1:1 mixture of ethanol and DI water. The solid was dried undervacuum overnight to afford 1.51 g (91%) of the title compound as a whitesolid. Data for 16d: R_(f)=0.47 (20% EtOAc/heptane); ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.11 (t, J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz, 2H), 3.84(s, 3H), 3.62-3.76 (m, 1H), 3.52-3.61 (m, 1H), 3.43 (dd, J=6.84, 9.96Hz, 1H), 2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz, 18H),0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2 (M+H⁺).

Example 18g(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one(16d)

To a solution of tricyclic enone 15d (2.0 g, 3.0 mmol, 1.0 equiv) inmethanol (15 mL) was added anhydrous potassium carbonate (141 mg, 7%w/w) and 10% Pd/C (294 mg, 50% wet, 15% w/w) and the mixture washydrogenated at atmospheric pressure of hydrogen gas while stirring atroom temperature overnight. The reaction was then filtered throughcelite, the residue washed with several portions of methanol, and thefiltrate concentrated to give a yellow oil. Triteration with heptanecaused formation of a small amount of precipitate that was filtered off.The filtrate was concentrated to give a viscous, yellow oil.Chromatography (0% to 3% ethyl acetate/heptane gradient) afforded 1.51 g(94%) of the title compound as white solid. Data for 16d: R_(f)=0.47(20% EtOAc/heptane); ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.11 (t, J=7.81Hz, 1H), 6.71 (d, J=8.20 Hz, 2H), 3.84 (s, 3H), 3.62-3.76 (m, 1H),3.52-3.61 (m, 1H), 3.43 (dd, J=6.84, 9.96 Hz, 1H), 2.10-3.08 (m, 8H),1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz, 18H), 0.01-0.18 (m, 12H); MS(ESI+) m/z 533.2 (M+H⁺).

Example 18h(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one(16d)

To a solution of tricyclic enone 15d (1.42 g, 2.15 mmol, 1.0 equiv) inmethanol (15 mL) was added anhydrous potassium bicarbonate (110 mg, 8%w/w) and 10% Pd/C (220 mg, 50% wet, 15% w/w) and the mixture washydrogenated at 10 psi of hydrogen gas while stirring at roomtemperature for 24 hours. The reaction was then charged with additionalanhydrous potassium bicarbonate (110 mg, 8% w/w) and 10% Pd/C (220 mg,50% wet, 15% w/w) and hydrogenated under 10 psi hydrogen gas whilestirring at room temperature for about 24 hours. The reaction was thenfiltered through celite, the residue washed with several portions ofmethanol, and the filtrate concentrated to give a yellow oil.Triteration with heptane caused formation of a small amount ofprecipitate that was filtered off, and the filtrate concentrated to give12.5 g of a viscous, yellow oil. Chromatography (0% to 10% ethylacetate/heptane gradient) afforded 722 mg (63%) of the title compound asa pale oil. Data for 16d: R_(f)=0.47 (20% EtOAc/heptane); ¹H NMR (400MHz, CHLOROFORM-d) δ 7.11 (t, J=7.81 Hz, 1H), 6.71 (d, J=8.20 Hz, 2H),3.84 (s, 3H), 3.62-3.76 (m, 1H), 3.52-3.61 (m, 1H), 3.43 (dd, J=6.84,9.96 Hz, 1H), 2.10-3.08 (m, 8H), 1.19-2.04 (m, 5H), 0.91 (d, J=8.98 Hz,18H), 0.01-0.18 (m, 12H); MS (ESI+) m/z 533.2 (M+H⁻).

Examples 18i-18s(3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-3a,4,9,9a-tetrahydro-1H-cyclopenta[b]naphthalen-2(3H)-one(16d)

The hydrogenation of tricyclic enone 15d to generate ketone 16d wasperformed using a 10% Pd/C (50% wet) catalyst and other reactionconditions provided in Table 1:

TABLE 1 Reaction conditions for the hydrogenation of tricyclic enone15d. H₂ % yield Ex. # Catalyst Base (wt %) Solvent pressure 16d i 15 wt% K₂CO₃ (5) MeOH 10 psi 76 j 15 wt % K₂CO₃ (5) EtOAc 10 psi 72 (x2) k 15wt % K₂CO₃ (5) THF 10 psi 102 (x2) l 15 wt % K₂CO₃ (5) THF 10 psi 100(x2) m 1 wt % KHCO₃ (2 × MeOH 10 psi 63 7.7) n 15 wt % KHCO₃ (2 × MeOHatm 79 7.7) o 15 wt % KHCO₃ (8.2) EtOH 10 psi 83 p 15 wt % KHCO₃ (7.4)EtOH atm 54 q 15 wt % K₂CO₃ (5) 2-Me- 10 psi 63 (x2) THF r 15 wt % K₂CO₃(5) EtOH 10 psi 64 s 15 wt % KHCO₃ (5) EtOH 10 psi 87 (x2)

Example 19a(1R,2R,3aS,9aS)-1-((R)-3,4-bis((tert-butyldimethylsilyl)oxy)butyl)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol(17c)

Sodium hydroxide (5.492 g in 28 mL of water, 20% solution in water, 10equiv) was added to a −10° C. solution of ketone 16d (7.318 g, 13.73mmol, 1.0 equiv) in absolute ethanol and the reaction was stirred undernitrogen for 30 minutes. Then, sodium borohydride (545 mg,14.42 mmol,1.05 equiv) was added in one portion and the reaction maintained at −10°C. for 1 hour with stirring. At that point, an additional portion ofsodium borohydride (545 mg, 14.42 mmol, 1.05 equiv) was added and thereaction stirred at −10° C. for 17 hours. The reaction was thencautiously quenched with addition of glacial acetic acid (10 mL),resulting in a pH of 6. This was diluted with brine (200 mL) and warmedto room temperature. The mixture was extracted with heptane (3×200 mL),the combined organic phases dried (MgSO₄) and concentrated to give ayellow oil. Chromatography (0% to 15% ethyl acetate/heptane gradient)afforded 5.359 g (73%) of the title compound as a viscous, colorlessoil. Data for 17c: R_(f)=0.53 (20% EtOAc/heptane); ¹H NMR (400 MHz,CDCl₃) δ 7.11 (t, J=7.91 Hz, 1H), 6.76 (dd, J=2.78, 7.76 Hz, 2H), 3.82(s, 3H), 3.62-3.78 (m, 2H), 3.51-3.60 (m, 1H), 3.39-3.49 (m, 1H),2.70-2.87 (m, 2H), 2.48 (ddd, J=6.59, 11.35, 14.57 Hz, 2H), 2.12-2.31(m, 2H), 1.84-1.97 (m, 1H), 1.44-1.80 (m, 5H), 1.22-1.32 (m, 1H),1.10-1.22 (m, 1H), 0.91 (s, 18H), 0.01-0.16 (m, 12H); MS (ESI+) m/z557.5 (M+Na⁺).

Example 19b(R)-4-((1R,2R,3aS,9aS)-2-hydroxy-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)butane-1,2-diol(17d)

Sodium hydroxide (648 mg in 3.2 mL of water, 20% solution in water, 16.2mmol, 10 equiv) was added to a −10° C. solution of ketone 16d (864 mg,1.62 mmol, 1.0 equiv) in absolute ethanol and the reaction was stirredunder nitrogen for 30 minutes. Then, sodium borohydride (68 mg, 1.80mmol, 1.1 equiv) was added in one portion and the reaction maintained at−10° C. for 1 hour with stirring. At that point, an additional portionof sodium borohydride (68 mg, 1.80 mmol, 1.1 equiv) was added and thereaction stirred at −10° C. for 17 hours. The reaction was thencautiously quenched with addition of 3 N aqueous HCl (10 mL) until thepH was about 1, the reaction was warmed to room temperature and stirred2 hours until homogenous. This was concentrated by rotary evaporation toremove the ethanol, diluted with brine (10 mL) and the resulting whiteslurry extracted with a solution of 10% ethanol/isopropyl acetate (3×20mL). The combined organic phases were dried (Na₂SO₄) and concentrated togive 530 mg of an off-white solid. The crude product was recrystallizedby dissolving in refluxing ethyl acetate (10 mL) and cooling back toroom temperature giving 432 mg (87%) of the title compound as a whitesolid. Data for 17d: R_(f)=0.18 (100% EtOAc); ¹H NMR (400 MHz, DMSO-d₆)δ 7.07 (t, J=7.87 Hz, 1H), 6.80 (d, J=8.42 Hz, 1H), 6.74 (d, J=7.32 Hz,1H), 4.48 (d, J=5.49 Hz, 1H), 4.44 (t, J=5.31 Hz, 1H), 4.37 (d, J=4.39Hz, 1H), 3.74 (s, 3H), 3.40-3.53 (m, 1H), 3.36-3.40 (m, 1H), 3.22-3.32(m, 2H), 2.64 (ddd, J=6.59, 8.51, 14.56 Hz, 2H), 2.32-2.47 (m, 2H),2.03-2.19 (m, 1H), 1.87-2.00 (m, 1H), 1.71-1.84 (m, 1H), 1.60-1.71 (m,1H), 1.46-1.60 (m, 1H), 1.22-1.40 (m, 2H), 1.01-1.14 (m, 1H), 0.84-1.01(m, 1H); MS (ESI+) m/z 329.2 (M+Na⁺).

Example 20a(R)-5-(2-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)ethyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane(18d)

Imidazole (1.017 g, 14.94 mmol, 1.5 equiv) andtert-butyl(chloro)diphenylsilane (3.557 g, 12.94 mmol, 1.3 equiv) wereadded to a stirred solution of alcohol 17c (5.326 g, 9.957 mmol, 1.0equiv) in anhydrous DMF, under nitrogen, and the mixture was then warmedto 50° C. for 40 hours. The reaction was then quenched with addition ofsaturated aqueous ammonium chloride (100 mL) and extracted with heptane(3×100 mL). The combined organic phases were washed with water, brineand concentrated to give a pale yellow oil. Chromatography (0% to 10%ethyl acetate/heptane gradient) afforded 7.186 g (93%) of the titlecompound as a viscous, colorless oil. Data for 18d: R_(f)=0.74 (20%EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 7.67 (dd, J=6.77, 14.46 Hz,4H), 7.30-7.49 (m, 6H), 7.11 (t, J=7.69 Hz, 1H), 6.69-6.83 (m, 2H),3.73-3.88 (m, 4H, contains s, 3H, 3.79), 3.53-3.65 (m, 1H), 3.43-3.52(m, 1H), 3.32-3.43 (m, 1H), 2.92 (dd, J=6.23, 14.65 Hz, 1H), 2.77 (dd,J=5.86, 14.28 Hz, 1H), 2.52 (dd, J=8.79, 14.28 Hz, 1H), 2.28 (dd,J=8.42, 14.65 Hz, 1H), 1.96 (sxt, J=8.06 Hz, 1H), 1.48-1.83 (m, 5H),1.14-1.45 (m, 3H), 1.03 (s, 9H), 0.90 (d, J=4.03 Hz, 18H), 0.06 (t,J=3.30 Hz, 12H).

Example 20b(1R,2R,3aS,9aS)-1-(2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol(18e)

PTSA.H₂O (15 mg, 0.082 mmol, 0.05 equiv) was added to a solution of 17d(500 mg, 1.53 mmol, 1.0 equiv) and 2,2-dimethoxypropane (0.40 mL, 3,2mmol, 2.0 equiv) in anhydrous DMF (5 mL), under nitrogen, and themixture was stirred at room temperature for 22 hours. The reaction wasthen quenched with addition of saturated aqueous sodium bicarbonate (5mL), diluted with water (5 mL) and extracted with ethyl acetate (3×10mL). The combined organic phases were washed with brine, dried (MgSO₄)and concentrated to give 997 mg of a light brown oil. Chromatography(25% to 60% ethyl acetate/heptane gradient) afforded 529 mg (94%) of thetitle compound as a colorless oil. Data for 18a: R_(f)=0.32 (50%EtOAc/heptane); ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.10 (t, J=7.87 Hz,1H), 6.76 (t, J=8.24 Hz, 2H), 3.96-4.17 (m, 2H), 3.80 (s, 3H), 3.64-3.75(m, 1H), 3.53 (t, J=7.51 Hz, 1H), 2.76 (ddd, J=6.23, 12.27, 14.46 Hz,2H), 2.41-2.59 (m, 2H), 2.19-2.33 (m, 1H), 2.09-2.19 (m, 1H), 2.05 (s,1H), 1.56-1.95 (m, 4H), 1.44-1.55 (m, 1H), 1.42 (s, 3H), 1.37 (s, 3H),1.21-1.32 (m, 1H), 1.06-1.19 (m, 1H); MS (ESI+) m/z 369.1 (M+Na⁺).

Example 20cTert-butyl(((1R,2R,3aS,9aS)-1-(2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)oxy)diphenylsilane(18f)

Imidazole (145 mg, 2.13 mmol, 1.4 equiv) andtert-butyl(chloro)diphenylsilane (501 mg, 1.82 mmol, 1.2 equiv) wereadded to a stirred solution of alcohol 18e (526 mg, 1.52 mmol, 1.0equiv) in anhydrous DMF (7.5 mL), under nitrogen, and the mixture wasthen warmed to 50° C. for 19 hours. The reaction was then quenched withwater (10 mL) and extracted with heptane (3×10 mL). The combined organicphases were washed with 14% aqueous sodium chloride and concentrated togive 989 mg of a pale yellow oil. Chromatography (0% to 10% ethylacetate/heptane gradient) afforded 882 mg (99%) of the title compound asa colorless oil. Data for 18f: R_(f)=0.55 (20% EtOAc/heptane); ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.69 (dt, J=6.59, 17.21 Hz, 4H), 7.32-7.49 (m,6H), 7.12 (t, J=7.69 Hz, 1H), 6.77 (t, J=8.06 Hz, 2H), 3.89-3.99 (m,2H), 3.72-3.84 (m, 4H), 3.25-3.43 (m, 1H), 2.89 (dd, J=6.23, 14.65 Hz,1H), 2.75 (dd, J=6.23, 14.28 Hz, 1H), 2.51 (dd, J=8.24, 14.10 Hz, 1H),2.34 (dd, J=8.06, 14.65 Hz, 1H), 1.48-2.08 (m, 7H), 1.24-1.46 (m, 7H),1.18 (td, J=4.94, 9.89 Hz, 1H), 1.04 (s, 9H).

Example 21a(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)butane-1,2-diol(19d)

Aqueous 3N hydrochloric acid (10 mL) was added to a solution of TBDMSether 18d (4.411 g, 5.704 mmol, 1.0 equiv) in THF (30 mL) and MeOH (10mL) and the reaction stirred at room temperature for 27 hours. Thereaction was then concentrated to remove the organic solvents, dilutedwith water (50 mL), and extracted with EtOAc (3×100 mL). The combinedorganic phases were washed with saturated aqueous sodium bicarbonate,brine, dried (Na₂SO₄) and concentrated to give a foamy oil.Chromatography (20% to 80% ethyl acetate/heptane gradient) afforded1.982 g (64%) of the title compound as a fluffy white solid. Data for19d: R_(f)=0.26 (40% EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 7.60-7.76(m, 4H), 7.32-7.49 (m, 6H), 7.12 (t, J=7.78 Hz, 1H), 6.77 (t, J=7.78 Hz,2H), 3.72-3.85 (m, 4H, contains s, 3H, 3.80), 3.48-3.59 (m, 2H),3.27-3.39 (m, 1H), 2.90 (dd, J=6.13, 14.74 Hz, 1H), 2.74 (dd, J=6.04,14.10 Hz, 1H), 2.50 (dd, J=8.24, 14.10 Hz, 1H), 2.34 (dd, J=7.78, 14.74Hz, 1H), 1.84-2.08 (m, 2H), 1.80 (s, 2H), 1.72 (td, J=8.03, 16.34 Hz,1H), 1.48-1.62 (m, 2H), 1.15-1.46 (m, 4H), 1.04 (s, 9H); MS (ESI+) m/z567.5 (M+Na⁺).

Example 21b(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)butane-1,2-diol(19d)

Tetra-n-butylammonium fluoride (2.75 mL, 2.75 mmol, 2.0 equiv, 1.0 Msolution in THF) was added to an ice-cold solution of TBDMS ether 18d(1.053 g, 1.362 mmol, 1.0 equiv) in THF (10 mL) and the reaction stirredat 0° C. for 3 hours. The reaction was then quenched with saturatedaqueous ammonium chloride (10 mL), diluted with water (10 mL) andextracted with ethyl acetate (3×20 mL). The combined organic phases weredried (Na₂SO₄) and concentrated to give 1.03 g of a yellow oil.Chromatography (30% to 100% ethyl acetate/heptane gradient) afforded 616mg (83%) of the title compound as a white, foamy solid. Data for 19d:R_(f)=0.26 (40% EtOAc/heptane); ¹H NMR (400 MHz, CHLOROFORM-d) δ7.60-7.76 (m, 4H), 7.32-7.49 (m, 6H), 7.12 (t, J=7.78 Hz, 1H), 6.77 (t,J=7.78 Hz, 2H), 3.72-3.85 (m, 4H, contains s, 3H, 3.80), 3.48-3.59 (m,2H), 3.27-3.39 (m, 1H), 2.90 (dd, J=6.13, 14.74 Hz, 1H), 2.74 (dd,J=6.04, 14.10 Hz, 1H), 2.50 (dd, J=8.24, 14.10 Hz, 1H), 2.34 (dd,J=7.78, 14.74 Hz, 1H), 1.84-2.08 (m, 2H), 1.80 (s, 2H), 1.72 (td,J=8.03, 16.34 Hz, 1H), 1.48-1.62 (m, 2H), 1.15-1.46 (m, 4H), 1.04 (s,9H); MS (ESI+) m/z 567.3 (M+Na⁺).

Example 21c(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)butane-1,2-diol(19d)

Aqueous hydrochloric acid (10 mL, 1 N solution) was added to a solutionof acetonide 18f (1.015 g, 1.735 mmol, 1.0 equiv) in THF (10 mL) and thereaction stirred at room temperature for 46 hours. It was then dilutedwith 14% aqueous sodium chloride (20 mL) and extracted with isopropylacetate (3×20 mL). The combined organic phases were washed withsaturated aqueous sodium bicarbonate (40 mL), 14% aqueous sodiumchloride (40 mL), dried (Na₂SO₄) and concentrated to give 1.066 g of acolorless oil. Chromatography (40% to 100% ethyl acetate/heptanegradient) afforded 670 mg (71%) of the title compound as a foamy whitesolid. Data for 19d: R_(f)=0.31 (50% EtOAc/heptane); ¹H NMR (400 MHz,CHLOROFORM-d) δ 7.58-7.81 (m, 4H), 7.31-7.51 (m, 6H), 7.11 (t, J=7.91Hz, 1H), 6.77 (t, J=7.62 Hz, 2H), 3.73-3.85 (m, 4H, contains s, 3H,3.80), 3.47-3.62 (m, 2H), 3.27-3.40 (m, 1H), 2.90 (dd, J=6.15, 14.65 Hz,1H), 2.74 (dd, J=6.15, 14.06 Hz, 1H), 2.50 (dd, J=8.20, 14.06 Hz, 1H),2.34 (dd, J=7.91, 14.65 Hz, 1H), 1.83-2.09 (m, 2H), 1.64-1.82 (m, 3H),1.48-1.62 (m, 2H), 1.14-1.46 (m, 4H), 0.96-1.11 (m, 9H); MS (ESI+) m/z567.2 (M+Na⁺).

Example 21d(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)butane-1,2-diol(19d)

Triethylamine trihydrofluoride (0.16 mL, 0.98 mmol, 3.0 equiv) was addedto an ice-cold solution of TBDMS ether 18d (253 mg, 0.327 mmol, 1.0equiv) in THF (2 mL) with stirring, under nitrogen. The reaction wasthen warmed to 50° C. for 18 hours at which point it was shown to becomplete by TLC. The reaction was quenched with saturated aqueousammonium chloride (2 mL), diluted with water (2 mL) and extracted withethyl acetate (3×4 mL). The combined organic phases were dried (Na₂SO₄)and concentrated to give 172 mg of a yellow oil. Chromatography (30% to100% ethyl acetate/heptane gradient) afforded 99 mg (58%) of the titlecompound as a white, foamy solid. Data for 19d: R_(f)=0.26 (40%EtOAc/heptane); ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.60-7.76 (m, 4H),7.32-7.49 (m, 6H), 7.12 (t, J=7.78 Hz, 1H), 6.77 (t, J=7.78 Hz, 2H),3.72-3.85 (m, 4H, contains s, 3H, 3.80), 3.48-3.59 (m, 2H), 3.27-3.39(m, 1H), 2.90 (dd, J=6.13, 14.74 Hz, 1H), 2.74 (dd, J=6.04, 14.10 Hz,1H), 2.50 (dd, J=8.24, 14.10 Hz, 1H), 2.34 (dd, J=7.78, 14.74 Hz, 1H),1.84-2.08 (m, 2H), 1.80 (s, 2H), 1.72 (td, J=8.03, 16.34 Hz, 1H),1.48-1.62 (m, 2H), 1.15-1.46 (m, 4H), 1.04 (s, 9H).

Example 21e(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)butane-1,2-diol(19d)

Pyridinium p-toluene sulfonate (5.52 g, 220 mmol) was added to asolution of TBDMS ether 18d (17 g, 221 mmol, 1.0 equiv) in ethanol (170mL) and the reaction stirred at 40° C. for 56 hours. The reaction wasthen quenched with 2 mL of pyridine, and the resulting mixtureconcentrated to remove the organic solvents. Chromatography (15% to 40%ethyl acetate/heptane gradient) afforded 9.48 g (78%) of the titlecompound as a fluffy white solid. Data for 19d: R_(f)=0.26 (40%EtOAc/heptane); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.60-7.76 (m, 4H),7.32-7.49 (m, 6H), 7.12 (t, J=7.78 Hz, 1H), 6.77 (t, J=7.78 Hz, 2H),3.72-3.85 (m, 4H, contains s, 3H, 3.80), 3.48-3.59 (m, 2H), 3.27-3.39(m, 1H), 2.90 (dd, J=6.13, 14.74 Hz, 1H), 2.74 (dd, J=6.04, 14.10 Hz,1H), 2.50 (dd, J=8.24, 14.10 Hz, 1H), 2.34 (dd, J=7.78, 14.74 Hz, 1H),1.84-2.08 (m, 2H), 1.80 (s, 2H), 1.72 (td, J=8.03, 16.34 Hz, 1H),1.48-1.62 (m, 2H), 1.15-1.46 (m, 4H), 1.04 (s, 9H); MS (ESI+) m/z 567.3(M+Na⁺).

Example 22(R)-4-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)-2-hydroxybutyl2,4,6-triisopropylbenzenesulfonate (20d)

Triethylamine (3.80 mL, 27.5 mmol, 4.0 equiv) and4-dimethylaminopyridine (168 mg, 1.374 mmol, 0.2 equiv) were added to asolution of diol 19d (3.744 g, 6.872 mmol, 1.0 equiv) in anhydrousmethylene chloride (30 mL) while stirring under nitrogen. The reactionwas then cooled to 0° C. and 2,4,6-triisopropylbenzenesulfonyl chloride(2.498 g, 8.247 mmol, 1.2 equiv) added drop-wise as a solution inanhydrous methylene chloride (10 mL). After stirring at this temperaturefor 15 hours, the reaction was quenched with addition of saturatedaqueous ammonium chloride (50 mL) and warmed to room temperature. Thetwo phases were separated and the aqueous phase extracted with methylenechloride (3×50 mL). The combined organics were dried (MgSO₄) andconcentrated to give a dark yellow oil. Chromatography (0% to 20% ethylacetate/heptane gradient) afforded 4.797 g (86%) of the title compoundas a white, foamy solid. Data for 20d: R_(f)=0.46 (20% EtOAc/heptane);¹H NMR (400 MHz, CDCl₃) δ 7.55-7.73 (m, 4H), 7.29-7.46 (m, 6H), 7.22 (s,2H), 7.11 (t, J=7.87 Hz, 1H), 6.75 (d, J=8.42 Hz, 2H), 4.15 (quin,J=6.68 Hz, 2H), 3.92 (dd, J=2.56, 9.89 Hz, 1H), 3.58-3.84 (m, 6H,contains s, 3H, 3.80), 2.81-3.03 (m, 2H), 2.71 (dd, J=6.23, 14.28 Hz,1H), 2.46 (dd, J=8.06, 14.28 Hz, 1H), 2.26-2.40 (m, 1H), 1.81-2.09 (m,3H), 1.69 (td, J=8.06, 16.11 Hz, 1H), 1.46-1.61 (m, 2H), 1.28 (m, 22H),1.01 (s, 9H); MS (ESI+) m/z 828.8 (M+NH₄ ⁺).

Example 23atert-butyl(((1R,2R,3aS,9aS)-5-methoxy-1-(2-((R)-oxiran-2-yl)ethyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)oxy)diphenylsilane(21c)

Anhydrous potassium carbonate (1.592 g, 11.52 mmol, 2.0 equiv) was addedto a solution of alcohol 20d (4.674 g, 5.762 mmol, 1.0 equiv) inanhydrous methanol (30 mL) and the mixture stirred under nitrogen for 1hour. The reaction was then concentrated, the residue triterated inmethylene chloride and filtered to remove the precipitate. The filtratewas concentrated, and the residue triterated in heptane, filtered toremove the precipitate and the filtrate concentrated to give 3.032 g(99%) of the title compound as a colorless oil. This material was deemedsufficiently pure to be carried forward. Data for 21c: R_(f)=0.50 (20%EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 7.59-7.77 (m, 4H), 7.32-7.49(m, 6H), 7.11 (t, J=7.69 Hz, 1H), 6.76 (t, J=8.24 Hz, 2H), 3.72-3.86 (m,4H, contains s, 3H, 3.80), 2.89 (dd, J=6.23, 14.65 Hz, 1H), 2.66-2.84(m, 3H), 2.50 (dd, J=8.06, 14.28 Hz, 1H), 2.35-2.44 (m, 1H), 2.32 (dd,J=8.06, 15.01 Hz, 1H), 1.92-2.05 (m, 1H), 1.79-1.90 (m, 1H), 1.22-1.77(m, 7H), 1.04 (s, 9H); MS (ESI+) m/z 549.5 (M+Na⁺).

Example 23btert-butyl(((1R,2R,3aS,9aS)-5-methoxy-1-(2-((R)-oxiran-2-yl)ethyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)oxy)diphenylsilane(21c)

Anhydrous potassium carbonate (14.14 g, 102.3 mmol, 2.0 equiv) was addedto a solution of alcohol 20d (41.5 g, 51.2 mmol, 1.0 equiv) in anhydrousmethanol (415 mL) and the mixture stirred under nitrogen for 24 hours.The reaction was then quenched with 14% aqueous sodium chloride solution(800 mL) and extracted with heptane (3×800 mL). The combined organicphases were washed with 14% aqueous sodium chloride solution (800 mL),dried (MgSO₄) and concentrated to give 26.3 g of a white waxy solid.Chromatography (0% to 10% ethyl acetate/heptane gradient) afforded 24.1g (89%) of the title compound (21c) as a white waxy solid. The 24.1 g of21c obtained above was warmed to a gentle reflux in heptane (240 mL, 10volumes) until dissolved, cooled first to room temperature and then to−20° C. After standing at that temperature overnight, white crystals hadformed that were filtered and dried under high vacuum to give 22.003 gof 21c (91% recovery). HPLC analysis showed that the white waxy solid21c material had a purity of 91.07%, while the recrystallized 21cmaterial had a purity of 96.59%. This recrystallization process wasrepeated again with 220 mL heptane giving 20.240 g (92% recovery) of 21cas a white crystalline product. HPLC analysis showed further enrichmentto a purity of 97.46%. The 20.240 g of 21c obtained above was warmed toa gentle reflux in heptane (200 mL, 10 volumes) until dissolved, cooledfirst to room temperature and then to −20° C. After standing at thattemperature overnight, white crystals had formed which were filtered anddried at 40° C. under high vacuum to give 19.308 g of 21c (95%recovery). HPLC analysis showed further enrichment to a purity of98.19%. Data for 21c: R_(f)=0.50 (20% EtOAc/heptane); mp=78.5-79.5° C.;¹H NMR (400 MHz, CHLOROFORM-d) δ 7.59-7.77 (m, 4H), 7.32-7.49 (m, 6H),7.11 (t, J=7.69 Hz, 1H), 6.76 (t, J=8.24 Hz, 2H), 3.72-3.86 (m, 4H,contains s, 3H, 3.80), 2.89 (dd, J=6.23, 14.65 Hz, 1H), 2.66-2.84 (m,3H), 2.50 (dd, J=8.06, 14.28 Hz, 1H), 2.35-2.44 (m, 1H), 2.32 (dd,J=8.06, 15.01 Hz, 1H), 1.92-2.05 (m, 1H), 1.79-1.90 (m, 1H), 1.22-1.77(m, 7H), 1.04 (s, 9H); IR (KBr pellet) 3427.7 (s), 3071.0 (m), 3049.8(m), 2959.6 (s), 2928.6 (s), 2858.7 (m), 1797.0 (w), 1584.5 (s), 1473.4(s), 1454.6 (m), 1428.1 (m), 1264.4 (s), 1109.4 (s), 1022.0 (m), 822.6(w), 783.1 (w), 743.9 (w), 703.8 (s), 613.5 (w) cm⁻¹; MS (ESI+) m/z549.5 (M+Na⁺); HPLC, Regis (S,S) Whelk-01 column (4.6×250 mm²), 5 μm;flow rate 1.0 mL/min; 210 nm; mobile phase 90:10 heptane/MTBE, 21cretention time: 20.14 min.

Example 24a(S)-1-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)heptan-3-ol(22b)

A slurry of epoxide 21c (56 mg, 0.11 mmol, 1.0 equiv) and copper(I)iodide (4.0 mg, 0.021 mmol, 0.2 equiv) in anhydrous ether (1.0 mL) thathad been cooled to −78° C. was treated drop-wise with n-butyllithium(0.28 mL, 0.70 mmol, 6.6 equiv, 2.5 M in hexanes) and the resultingmixture slowly warmed to −40° C. over 30 minutes while stirring undernitrogen. The cloudy yellow mixture turned almost black in color duringthis time and the reaction was shown to be complete by TLC. This wasthen quenched with addition of saturated aqueous ammonium chloride (5mL) and warmed to room temperature. The deep blue aqueous layer wasextracted with ethyl acetate (3×5 mL). The combined organic phases werewashed with brine, dried (MgSO₄) and concentrated to give 60 mg of acolorless oil. Chromatography (0% to 20% ethyl acetate/heptane gradient)afforded 52 mg (84%) of the title compound as a colorless oil. Data for22b: R_(f)=0.42 (20% EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 7.59-7.77(m, 4H), 7.31-7.51 (m, 6H), 7.11 (t, J=7.81 Hz, 1H), 6.71-6.81 (m, 2H),3.73-3.85 (m, 4H, contains s, 3H, 3.80), 3.44 (br. s., 1H), 2.91 (dd,J=6.25, 14.45 Hz, 1H), 2.75 (dd, J=6.25, 14.45 Hz, 1H), 2.50 (dd,J=8.20, 14.06 Hz, 1H), 2.32 (dd, J=8.01, 14.65 Hz, 1H), 1.82-2.05 (m,2H), 1.65-1.77 (m, 1H), 1.50-1.62 (m, 2H), 1.15-1.47 (m, 13H), 1.04 (s,9H), 0.92 (t, J=7.03 Hz, 3H); MS (ESI+) m/z 607.2 (M+Na⁺).

Example 24b(S)-1-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)hexan-3-ylacetate (22c)

A slurry of epoxide 21c (3.3 g, 6.3 mmol, 1.0 equiv) and copper(I)iodide (148 mg, 0.78 mmol, 0.013 equiv) in methyl tert-butyl ether (35.0mL) that had been cooled to −40° C. was treated drop-wise withn-butyllithium (11.4 mL, 17.1 mmol, 2.74 equiv, 1.5 M solution inhexanes) and the resulting mixture stirred under nitrogen. The cloudyyellow mixture turned almost black in color during this time and thereaction was shown to be complete by TLC. This was then treated withaddition of ethyl acetate and warmed to room temperature then quenchedwith aqueous ammonium chloride (75 mL). The deep blue aqueous layer wasextracted with ethyl acetate (2×75 mL). The combined organic phases wereconcentrated to give a colorless oil. Chromatography (0% to 2% ethylacetate/heptane gradient) afforded 3.3 g (88%) of the title compound asa colorless oil. Data for 22c: R_(f)=0.64 (20% EtOAc/heptane); ¹H NMR(400 MHz, CHLOROFORM-d) δ 7.60-7.73 (m, 4H), 7.31-7.48 (m, 6H), 7.11 (t,J=7.69 Hz, 1H), 6.77 (dd, J=7.87, 16.30 Hz, 2H), 4.80 (d, J=5.86 Hz,1H), 3.68-3.83 (m, 4H), 2.87 (dd, J=6.23, 14.65 Hz, 1H), 2.73 (dd,J=6.23, 13.92 Hz, 1H), 2.48 (dd, J=8.24, 14.10 Hz, 1H), 2.30 (dd,J=8.06, 15.01 Hz, 1H), 1.89-2.06 (m, 4H), 1.74-1.87(m, 1H), 1.61-1.74(m, 1H), 1.13-1.60 (m, 14H), 1.03 (s, 9H), 0.84-0.94 (m, 3H); MS (ESI+)m/z 649.4 (M+Na⁺).

Example 24cS)-1-((1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-1-yl)heptan-3-ol(22b)

To a solution of acetate 22c (3.3 g, 5.3 mmol, 1 equiv) in methanol (90mL) was added anhydrous potassium carbonate (3.5 g, 25.4 mmol, 4.8equiv) and DI water (10 mL). The reaction was stirred at 60° C. forthree hours and then cooled to room temperature overnight. At that pointthe reaction was deemed complete by TLC and the solvent was removedunder reduced pressure. The crude residue was extracted withdichloromethane (100 mL), the organic layer passed through filter paperto remove the resulting white solid, and the filtrate was concentratedto give 3.12 g of a pale yellow solid (quantitative). Data for 22c:R_(f)=0.42 (20% EtOAc/heptane); ¹H NMR (400 MHz, CHLOROFORM-d) δ7.59-7.77 (m, 4H), 7.31-7.51 (m, 6H), 7.11 (t, J=7.81 Hz, 1H), 6.71-6.81(m, 2H), 3.73-3.85 (m, 4H, contains s, 3H, 3.80), 3.44 (br. s., 1H),2.91 (dd, J=6.25, 14.45 Hz, 1H), 2.75 (dd, J=6.25, 14.45 Hz, 1H), 2.50(dd, J=8.20, 14.06 Hz, 1H), 2.32 (dd, J=8.01, 14.65 Hz, 1H), 1.82-2.05(m, 2H), 1.65-1.77 (m, 1H), 1.50-1.62 (m, 2H), 1.15-1.47 (m, 13H), 1.04(s, 9H), 0.92 (t, J=7.03 Hz, 3H).

Example 25(1R,2R,3aS,9aS)-2-((tert-butyldiphenylsilyl)oxy)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-ol(23a)

A solution of n-butyllithium (6.80 mL, 17.0 mmol, 8.2 equiv, 2.5 M inhexanes) was added drop-wise to a −20° C. solution of diphenylphosphine(2.714 g, 14.58 mmol, 7.0 equiv) in THF (25 mL), under nitrogen, andstirred at that temperature for 30 minutes. Then, approximately ⅔ ofthis solution was cannulated into a solution of methyl ether 22b in THF(5 mL) at room temperature and the resultant mixture was heated toreflux for 2 hours while stirring, under nitrogen. The reaction was thencooled to room temperature, the remainder of then-butyllithium/diphenylphosphine solution was cannulated over and thereaction was heated back to reflux for 17 hours. At this point, thereaction was cooled in an ice bath and cautiously quenched with additionof 3 M aqueous hydrochloric acid until the pH is acidic. The organiclayer was separated and the aqueous phase extracted with ethyl acetate(3×30 mL). The combined organic phases were washed with brine, dried(Na₂SO₄) and concentrated to give 4.3 g of a colorless oil.Chromatography (0% to 40% ethyl acetate/heptane gradient) afforded 1.101g (93%) of the title compound as a white, foamy solid. Data for 23a:R_(f)=0.29 (20% EtOAc/heptane); ¹H NMR (400 MHz, CDCl₃) δ 7.70 (dd,J=7.32, 17.94 Hz, 4H), 7.32-7.51 (m, 6H), 6.96-7.06 (m, 1H), 6.75 (d,J=7.32 Hz, 1H), 6.67 (d, J=8.06 Hz, 1H), 3.82 (q, J=6.84 Hz, 1H), 3.49(br. s., 1H), 2.84 (dd, J=6.23, 14.65 Hz, 1H), 2.75 (dd, J=5.86, 14.28Hz, 1H), 2.51 (dd, J=8.24, 14.10 Hz, 1H), 2.34 (dd, J=7.87, 14.46 Hz,1H), 2.02 (dd, J=7.87, 15.93 Hz, 1H), 1.91 (td, J=6.36, 12.54 Hz, 1H),1.73 (quin, J=8.06 Hz, 1H), 1.50-1.65 (m, 2H), 1.15-1.49 (m, 13H), 1.07(s, 9H), 0.87-0.97 (m, 3H); MS (ESI+) m/z 593.3 (M+H⁺).

Example 26a(1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol(24a)

Tetra-n-butylammonium fluoride (2.90 mL, 2.90 mmol, 1.5 equiv, 1.0 Msolution in THF) was added to a solution of TBDPS-ether 23a (1.083 g,1.897 mmol, 1.0 equiv) in anhydrous THF, under nitrogen, and the mixturestirred at room temperature for 22 hours. Analysis by TLC indicated thatthe reaction was not complete, so it was fitted with a water-cooledcondenser and heated to 50° C. for 3.5 hours. The reaction was thenquenched with 14% aqueous sodium chloride (20 mL) and extracted withethyl acetate (3×15 mL). The combined organic phases were dried (Na₂SO₄)and concentrated to give 1.375 g of an amber oil. Chromatography (12% to100% ethyl acetate/heptane gradient) afforded 484 mg (77%) of the titlecompound as a white foam. Data for 24a: R_(f)=0.12 (50% EtOAc/heptane);¹H NMR (400 MHz, CHLOROFORM-d) δ 6.95 (t, J=7.51 Hz, 1H), 6.66 (dd,J=7.69, 13.55 Hz, 2H), 6.59 (br. s., 1H), 3.61-3.77 (m, 1H), 3.57 (br.s., 1H), 3.02 (br. s., 1H), 2.58-2.76 (m, 2H), 2.34-2.56 (m, 3H),2.17-2.30 (m, 1H), 2.03-2.14 (m, 1H), 1.79-1.93 (m, 1H), 1.64 (d, J=7.32Hz, 2H), 1.38-1.56 (m, 4H), 1.16-1.37 (m, 7H), 1.10 (q, J=10.62 Hz, 1H),0.85-0.96 (m, 3H); MS (ESI+) m/z 355.2 (M+Na⁺).

Example 26b(1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol(24a)

Triethylamine Trihydrofluoride (4.57 g, 28.3 mmol, 3.7 equiv) was addedin portions to a solution of TBDPS-ether 23a (4.4 g, 7.7 mmol, 1.0equiv) in anhydrous THF (45 mL), under nitrogen, and the mixture stirredat 62° C. for 5 days. Analysis by TLC indicated that the reaction wascomplete. The reaction was then quenched with 10% aqueous potassiumbicarbonate (35 mL) and extracted with ethyl acetate (2×35 mL). Thecombined organic phases were concentrated to give 5.37 g of oil.Chromatography (25% to 100% ethyl acetate/heptane gradient) afforded1.84 g (72%) of the title compound as white foam. Data for 24a:R_(f)=0.12 (50% EtOAc/heptane); ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.95(t, J=7.51 Hz, 1H), 6.66 (dd, J=7.69, 13.55 Hz, 2H), 6.59 (br. s., 1H),3.61-3.77 (m, 1H), 3.57 (br. s., 1H), 3.02 (br. s., 1H), 2.58-2.76 (m,2H), 2.34-2.56 (m, 3H), 2.17-2.30 (m, 1H), 2.03-2.14 (m, 1H), 1.79-1.93(m, 1H), 1.64 (d, J=7.32 Hz, 2H), 1.38-1.56 (m, 4H), 1.16-1.37 (m, 7H),1.10 (q, J=10.62 Hz, 1H), 0.85-0.96 (m, 3H); MS (ESI+) m/z 355.2(M+Na⁺).

Example 26c(1R,2R,3aS,9aS)-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol(24a)

Hydrochloric acid (12 mL, 3 N) was added to a solution of TBDPS-ether23a (4.4 g, 7.7 mmol) in methanol (40 mL) and the mixture stirred at 62°C. for 22 hrs. Analysis by TLC indicated that the reaction was complete.The reaction was concentrated to give 4.95 g of colorless oil.Chromatography (5% to 40% ethyl acetate/heptane gradient) afforded 1.48g (58%) of the title compound as white foam. Data for 24a: R_(f)=0.12(50% EtOAc/heptane); ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.91-6.99 (m,1H), 6.66-6.72 (m, 1H), 6.61-6.66 (m, 1H), 3.63-3.73 (m, 1H), 3.53-3.63(m, 1H), 2.57-2.75 (m, 2H), 2.33-2.51 (m, 2H), 2.16-2.30 (m, 1H),2.05-2.15 (m, 1H), 1.79-1.92 (m, 1H), 1.18-1.71 (m, 13 H), 1.04-1.15 (m,1H), 0.83-0.93 (m, 3H); MS (ESI+) m/z 355.2 (M+Na⁺).

Example 27 ethyl2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)acetate(25a)

Ethyl bromoacetate was added drop-wise to a slurry of benzindene triol24a (500 mg, 1.504 mmol, 1.0 equiv), anhydrous potassium carbonate (312mg, 2.26 mmol, 1.5 equiv) and anhydrous potassium iodide (25 mg, 0.15mmol, 0.1 equiv) in acetone (20 mL) and the reaction was heated toreflux while stirring, under nitrogen for 16 hours. The reaction wasthen cooled to room temperature, diluted with heptane (10 mL) andfiltered through celite. The celite was rinsed with ethyl acetate (3×30mL) and the filtrate was concentrated to give a pale oil. Chromatography(10% to 80% ethyl acetate/heptane gradient) afforded 610 mg (96%) of thetitle compound as a colorless oil. Data for 25a: R_(f)=0.15 (50%EtOAc/heptane); ¹H NMR ¹H NMR (400 MHz, CDCl₃) δ 7.07 (t, J=7.87 Hz,1H), 6.81 (d, J=7.32 Hz, 1H), 6.64 (d, J=7.69 Hz, 1H), 4.62 (s, 2H),4.27 (q, J=7.32 Hz, 2H), 3.76 (dt, J=6.04, 9.61 Hz, 1H), 3.55-3.70 (m,J=4.40 Hz, 1H), 2.89 (dd, J=5.86, 14.65 Hz, 1H), 2.76 (dd, J=6.23, 14.28Hz, 1H), 2.56 (dd, J=6.59, 15.01 Hz, 1H), 2.46 (dd, J=6.59, 14.28 Hz,1H), 2.11-2.34 (m, 4H), 1.89 (tt, J=6.50, 9.98 Hz, 1H), 1.24-1.75 (m,16H), 1.12-1.23 (m, 1H), 0.84-0.99 (m, 3H); MS (ESI+) m/z 419.3 (M+H⁺).

Example 282-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)aceticacid (I)

Potassium hydroxide (5.623 g in 19 mL water, 30% solution in water,100.2 mmol, 5.0 equiv) was added to a solution of ethyl ester 25a(8.390g, 20.04 mmol, 1.0 equiv) in ethanol (100 mL) and stirred at roomtemperature, under nitrogen for 90 minutes. The reaction was thenconcentrated under reduced pressure to remove the ethanol, diluted withwater (50 mL) and extracted with ethyl acetate (50 mL) to remove organicimpurities. The aqueous layer was acidified to pH 2-3 by addition of 3 Naqueous hydrochloric acid and extracted with ethyl acetate (3×100 mL).The combined organic phases were treated with activated charcoal (800mg) and heated to reflux for 1 hour, cooled to room temperature,filtered through celite and concentrated to give 8.2 g of the titlecompound as an off-white solid. This material was moved forward to thenext step crude and was not characterized further. Data for I:R_(f)=0.27 (90:10:1 methylene chloride/methanol/acetic acid).

Example 292-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)aceticacid diethanolamine salt (I, diethanolamine salt)

A solution of treprostinil I (7.83 g, 20.1 mmol, 1.0 equiv) in ethylacetate (250 mL) was treated with a solution of diethanolamine (2.11 g,20.1 mmol, 1.0 equiv) in anhydrous ethanol (32 mL) and the resultingslurry heated to reflux for 15 minutes, at which point everything wentinto solution. This was allowed to slowly cool to room temperature over18 hours resulting in formation of a white crystalline solid. The solidwas filtered, rinsed with ethyl acetate (2×100 mL), and dried for 24hours at 50° C. under vacuum to give 7.552 g (76%) of the title compoundas a white powder.

Example 302-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)aceticacid (I)

A solution of the diethanolamine salt of Formula I (5.775 g, 11.65 mmol,1.0 equiv) in water (60 mL) was treated with aqueous hydrochloric acid(2.11 g, 20.1 mmol, 1.0 equiv) in anhydrous ethanol (32 mL) and theresulting slurry heated to reflux for 15 minutes, at which pointeverything went into solution. This was allowed to slowly cool to roomtemperature over 18 hours resulting in formation of a white crystallinesolid. The solid was filtered, rinsed with ethyl acetate (2×100 mL), anddried for 24 hours at 50° C. under vacuum to give 7.552 g (76%) of thetitle compound as a white powder. Data for I: ¹H NMR (400 MHz,CHLOROFORM-d) d 7.07 (t, J=7.88 Hz, 1H), 6.82 (d, J=7.69 Hz, 1H), 6.68(d, J=8.43 Hz, 1H), 4.58-4.72 (m, 2H), 4.40 (br. s., 3H), 3.73 (dt,J=6.23, 9.34 Hz, 1H), 3.64 (d, J=3.66 Hz, 1H), 2.76 (ddd, J=6.23, 14.20,19.87 Hz, 2H), 2.61 (dd, J=6.04, 14.84 Hz, 1H), 2.48 (dd, J=6.23, 14.29Hz, 1H), 2.20-2.36 (m, 1H), 2.10-2.20 (m, 1H), 1.82-1.98 (m, 1H),1.52-1.76 (m, 4H), 1.40-1.52 (m, 3H), 1.21-1.40 (m, 6H), 1.08-1.21 (m,1H), 0.92 (t, J=6.60 Hz, 3H); MS (ESI+) m/z 413.2 (M+Na+); HPLC, SynergiHydro RP column (4.6×250 mm2), 5 mm; flow rate 2.0 mL/min; 277 nm;mobile phase water (60%):acetonitrile (40%): trifluoroacetic acid(0.1%); retention time, 39.12 min (98.0%, I), retention time, 41.05 min(1.2%,2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((R)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)aceticacid).

Example 31a2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)aceticacid sodium salt (I, sodium salt)

A solution of the compound of Formula I (1 equiv) will be dissolved indistilled ethanol at 30-50° C. and then cooled to 15-25° C. The solutionwill then be neutralized with a solution of sodium hydroxide (1 molarsolution in ethanol) using a glass electrode to detect the point ofequivalence (to pH value 9.8-10.2). The solution will be filtered, andthe filtrate concentrated to give the crude sodium salt of the compoundof Formula I. This may optionally be recrystallized from acetone/wateror another appropriate solvent system to furnish a pure form of thetitle compound.

Example 31b2-(((1R,2R,3aS,9aS)-2-hydroxy-1-((S)-3-hydroxyoctyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)aceticacid sodium salt (I, sodium salt)

A solution of ethyl ester 25a (1 equiv.) will be dissolved in distilledmethanol and aq. NaOH (1 equiv., 1 molar solution) will be added andstirred at an appropriate temperature until the salt formation iscomplete. The reaction will then be concentrated to give crude sodiumsalt of the compound of Formula I. This may optionally be recrystallizedfrom acetone/water or another appropriate solvent system to furnish apure form of the title compound.

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1.-103. (canceled)
 104. A compound of Formula 21

wherein R¹ is C₁₋₆ alkyl and each R³ is independently C₁₋₆ alkyl orphenyl.
 105. The compound of claim 104, wherein R¹ is methyl, ethyl,propyl, iso-propyl, butyl, sec-butyl, or tert-butyl.
 106. The compoundof claim 104, wherein the —OSi(R³)₃ group is selected from


107. The compound of claim 104, wherein R¹ is methyl and the —OSi(R³)₃group is 108-117. (canceled)